%0 Journal Article %J Cell %D 2023 %T S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis %A Deng, Liwen %A Costa, Flavia %A Blake, Kimbria J %A Choi, Samantha %A Chandrabalan, Arundhasa %A Yousuf, Muhammad Saad %A Shiers, Stephanie %A Dubreuil, Daniel %A Vega-Mendoza, Daniela %A Rolland, Corinne %A Deraison, Celine %A Voisin, Tiphaine %A Bagood, Michelle D %A Wesemann, Lucia %A Frey, Abigail M %A Palumbo, Joseph S %A Wainger, Brian J %A Gallo, Richard L %A Leyva-Castillo, Juan-Manuel %A Vergnolle, Nathalie %A Price, Theodore J %A Ramachandran, Rithwik %A Horswill, Alexander R %A Chiu, Isaac M %X Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch. %B Cell %V 186 %P 5375-5393.e25 %8 2023 Nov 22 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/37995657?dopt=Abstract %R 10.1016/j.cell.2023.10.019 %0 Journal Article %J Pain %D 2023 %T Neuronal-immune axis alters pain and sensory afferent damage during dental pulp injury %A Ozge Erdogan %A Michot, Benoit %A Xia, Jinya %A Alabdulaaly, Lama %A Yesares Rubi, Pilar %A Ha, Vivian %A Chiu, Isaac M %A Gibbs, Jennifer L %X Dental pulp tissue is densely innervated by afferent fibers of the trigeminal ganglion. When bacteria cause dental decay near the pulpal tissue, a strong neuronal and immune response occurs, creating pulpitis, which is associated with severe pain and pulp tissue damage. Neuroimmune interactions have the potential to modulate both the pain and pathological outcome of pulpitis. We first investigated the role of the neuropeptide calcitonin gene-related peptide (CGRP), released from peptidergic sensory afferents, in dental pain and immune responses by using Calca knockout (Calca-/-) and wild-type (Calca+/+) mice, in a model of pulpitis by creating a mechanical exposure of the dental pulp horn. We found that the neuropeptide CGRP, facilitated the recruitment of myeloid cells into the pulp while also increasing spontaneous pain-like behavior 20% to 25% at an early time point. Moreover, when we depleted neutrophils and monocytes, we found that there was 20% to 30% more sensory afferent loss and increased presence of bacteria in deeper parts of the tissue, whereas there was a significant reduction in mechanical pain response scores compared with the control group at a later time point. Overall, we showed that there is a crosstalk between peptidergic neurons and neutrophils in the pulp, modulating the pain and inflammatory outcomes of the disease. %B Pain %8 2023 Oct 30 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/37903298?dopt=Abstract %R 10.1097/j.pain.0000000000003029 %0 Journal Article %J J Endod %D 2023 %T Dynamics of Innate Immune Response in Bacteria-Induced Mouse Model of Pulpitis %A Ozge Erdogan %A Xia, Jingya %A Chiu, Isaac M %A Gibbs, Jennifer L %X INTRODUCTION: During pulpitis, as bacteria penetrate deeper into the dentin and pulp tissue, a pulpal innate immune response is initiated. However, the kinetics of the immune response, how this relates to bacterial infiltration during pulpitis and an understanding of the types of immune cells in the pulp is limited. METHODS: Dental pulp exposure in the molars of mice was used as an animal model of pulpitis. To investigate the kinetics of immune response, pulp tissue was collected from permanent molars at different time points after injury (baseline, day 1, and day 7). Flow cytometry analysis of CD45+ leukocytes, including macrophages, neutrophils monocytes, and T cells, was performed. 16S in situ hybridization captured bacterial invasion of the pulp, and immunohistochemistry for F4/80 investigated spatial and morphological changes of macrophages during pulpitis. Data were analyzed using two-way ANOVA with Tukey's multiple comparisons. RESULTS: Bacteria mostly remained close to the injury site, with some expansion towards noninjured pulp horns. We found that F4/80+ macrophages were the primary immune cell population in the healthy pulp. Upon injury, CD11b + Ly6Ghigh neutrophils and CD11b + Ly6GintLy6Cint monocytes constituted 70-90% of all immune populations up to 7 days after injury. Even though there was a slight increase in T cells at day 7, myeloid cells remained the main drivers of the immune response during the seven-day time period. CONCLUSIONS: As bacteria proliferate within the pulp chamber, innate immune cells, including macrophages, neutrophils, and monocytes, predominate as the major immune populations, with some signs of transitioning to an adaptive immune response. %B J Endod %8 2023 Sep 09 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/37678750?dopt=Abstract %R 10.1016/j.joen.2023.08.019 %0 Journal Article %J Cell Mol Immunol %D 2023 %T The role of cellular and molecular neuroimmune crosstalk in gut immunity %A Yang, Daping %A Almanzar, Nicole %A Chiu, Isaac M %X The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by the immune system. These two systems critically coordinate the sensations of and adaptations to dietary, microbial, and damaging stimuli from the external and internal microenvironment during tissue homeostasis and inflammation. The brain receives and integrates ascending sensory signals from the gut and transduces descending signals back to the gut via autonomic neurons. Neurons regulate intestinal immune responses through the action of local axon reflexes or through neuronal circuits via the gut-brain axis. This neuroimmune crosstalk is critical for gut homeostatic maintenance and disease resolution. In this review, we discuss the roles of distinct types of gut-innervating neurons in the modulation of intestinal mucosal immunity. We will focus on the molecular mechanisms governing how different immune cells respond to neural signals in host defense and inflammation. We also discuss the therapeutic potential of strategies targeting neuroimmune crosstalk for intestinal diseases. %B Cell Mol Immunol %8 2023 Jun 19 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/37336989?dopt=Abstract %R 10.1038/s41423-023-01054-5 %0 Journal Article %J Neuron %D 2023 %T Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration %A Neel, Dylan V %A Basu, Himanish %A Gunner, Georgia %A Bergstresser, Matthew D %A Giadone, Richard M %A Chung, Haeji %A Miao, Rui %A Chou, Vicky %A Brody, Eliza %A Jiang, Xin %A Lee, Edward %A Watts, Michelle E %A Marques, Christine %A Held, Aaron %A Wainger, Brian %A Lagier-Tourenne, Clotilde %A Zhang, Yong-Jie %A Petrucelli, Leonard %A Young-Pearse, Tracey L %A Chen-Plotkin, Alice S %A Rubin, Lee L %A Lieberman, Judy %A Chiu, Isaac M %X Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration. %B Neuron %8 2023 Mar 03 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/36917977?dopt=Abstract %R 10.1016/j.neuron.2023.02.019 %0 Journal Article %J Nature %D 2023 %T An airway-to-brain sensory pathway mediates influenza-induced sickness %A Bin, Na-Ryum %A Prescott, Sara L %A Horio, Nao %A Wang, Yandan %A Chiu, Isaac M %A Liberles, Stephen D %K Animals %K Blood-Brain Barrier %K Brain %K Dinoprostone %K Humans %K Influenza, Human %K Mice %K Sensory Receptor Cells %X Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes1,2. On infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons3,4; yet, the responding neural circuits and neuro-immune interaction mechanisms that evoke sickness behaviour during naturalistic infections remain unclear. Over-the-counter medications such as aspirin and ibuprofen are widely used to alleviate sickness and act by blocking prostaglandin E2 (PGE2) synthesis5. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons2. Here, using genetic tools that broadly cover a peripheral sensory neuron atlas, we instead identified a small population of PGE2-detecting glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behaviour in mice. Ablating petrosal GABRA1 neurons or targeted knockout of PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake and mobility during early-stage infection and improves survival. Genetically guided anatomical mapping revealed that petrosal GABRA1 neurons project to mucosal regions of the nasopharynx with increased expression of cyclooxygenase-2 after infection, and also display a specific axonal targeting pattern in the brainstem. Together, these findings reveal a primary airway-to-brain sensory pathway that detects locally produced prostaglandins and mediates systemic sickness responses to respiratory virus infection. %B Nature %V 615 %P 660-667 %8 2023 Mar %G eng %N 7953 %1 http://www.ncbi.nlm.nih.gov/pubmed/36890237?dopt=Abstract %R 10.1038/s41586-023-05796-0 %0 Journal Article %J Nature %D 2023 %T Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion %A Pinho-Ribeiro, Felipe A %A Deng, Liwen %A Dylan V. Neel %A Ozge Erdogan %A Basu, Himanish %A Yang, Daping %A Choi, Samantha %A Alec J. Walker %A Simone Carneiro-Nascimento %A Kathleen He %A Glendon Wu %A Beth Stevens %A Kelly S. Doran %A Levy, Dan %A Isaac M. Chiu %X The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2 . Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, afecting more than 2.5 million people a year3–5 . How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specifc RAMP1 defciency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP–RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis. %B Nature %G eng %0 Journal Article %J Cell %D 2023 %T Immunity to the microbiota promotes sensory neuron regeneration %A Enamorado, Michel %A Kulalert, Warakorn %A Han, Seong-Ji %A Rao, Indira %A Delaleu, Jérémie %A Link, Verena M %A Yong, Daniel %A Smelkinson, Margery %A Gil, Louis %A Nakajima, Saeko %A Linehan, Jonathan L %A Bouladoux, Nicolas %A Wlaschin, Josette %A Kabat, Juraj %A Kamenyeva, Olena %A Deng, Liwen %A Gribonika, Inta %A Chesler, Alexander T %A Chiu, Isaac M %A Le Pichon, Claire E %A Belkaid, Yasmine %K Animals %K Axons %K Interleukin-17 %K Mice %K Microbiota %K Nerve Regeneration %K Sensory Receptor Cells %K Th17 Cells %X Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process. %B Cell %V 186 %P 607-620.e17 %8 2023 Feb 02 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/36640762?dopt=Abstract %R 10.1016/j.cell.2022.12.037 %0 Journal Article %J Pain %D 2022 %T Interactions between nociceptor sensory neurons and microbial pathogens in pain %A Staurengo-Ferrari, Larissa %A Deng, Liwen %A Chiu, Isaac M %K Humans %K Nociceptors %K Pain %K Sensory Receptor Cells %B Pain %V 163 %P S57-S68 %8 2022 11 01 %G eng %N Suppl 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/36252233?dopt=Abstract %R 10.1097/j.pain.0000000000002721 %0 Journal Article %J Cell %D 2022 %T Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection %A Yang, Daping %A Jacobson, Amanda %A Meerschaert, Kimberly A %A Sifakis, Joseph Joy %A Wu, Meng %A Chen, Xi %A Yang, Tiandi %A Zhou, Youlian %A Anekal, Praju Vikas %A Rucker, Rachel A %A Sharma, Deepika %A Sontheimer-Phelps, Alexandra %A Wu, Glendon S %A Deng, Liwen %A Anderson, Michael D %A Choi, Samantha %A Neel, Dylan %A Lee, Nicole %A Kasper, Dennis L %A Jabri, Bana %A Huh, Jun R %A Johansson, Malin %A Thiagarajah, Jay R %A Riesenfeld, Samantha J %A Chiu, Isaac M %X Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection. %B Cell %8 2022 Oct 11 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/36243004?dopt=Abstract %R 10.1016/j.cell.2022.09.024 %0 Journal Article %J Curr Opin Immunol %D 2022 %T Editorial overview: Special section neuroimmunology: Neuroimmune interactions in health and disease %A Chiu, Isaac M %A Liblau, Roland %B Curr Opin Immunol %V 77 %P 102232 %8 2022 Jul 02 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/35792467?dopt=Abstract %R 10.1016/j.coi.2022.102232 %0 Journal Article %J Neuron %D 2022 %T Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems %A Chen, Xinhong %A Ravindra Kumar, Sripriya %A Adams, Cameron D %A Yang, Daping %A Wang, Tongtong %A Wolfe, Damien A %A Arokiaraj, Cynthia M %A Ngo, Victoria %A Campos, Lillian J %A Griffiths, Jessica A %A Ichiki, Takako %A Mazmanian, Sarkis K %A Osborne, Peregrine B %A Keast, Janet R %A Miller, Cory T %A Fox, Andrew S %A Chiu, Isaac M %A Gradinaru, Viviana %X Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice. %B Neuron %8 2022 May 23 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/35643078?dopt=Abstract %R 10.1016/j.neuron.2022.05.003 %0 Journal Article %J Immunol Rev %D 2022 %T Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis %A Neel, Dylan V %A Basu, Himanish %A Gunner, Georgia %A Chiu, Isaac M %X In the central nervous system (CNS), execution of programmed cell death (PCD) is crucial for proper neurodevelopment. However, aberrant activation of these pathways in adult CNS leads to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. In ALS, a fatal neuromuscular disorder marked by progressive death of lower and upper motor neurons, several cell types in the CNS express machinery for multiple PCD pathways. The specific cell types engaging PCD, and ultimate mechanisms by which neuronal death occurs in ALS are not well defined. Here, we provide an overview of different PCD pathways implicated in ALS. We also examine immune activation in ALS and differentiate apoptosis from necrotic mechanisms based on downstream immunological consequences. Lastly, we highlight therapeutic strategies that target cell death pathways in the treatment of neurodegeneration and inflammation in ALS. %B Immunol Rev %8 2022 May 07 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/35524757?dopt=Abstract %R 10.1111/imr.13083 %0 Journal Article %J Neuron %D 2022 %T A neuropeptide regulates immunity across species %A Deng, Liwen %A Chiu, Isaac M %K Central Nervous System Depressants %K Nervous System %K Neurons %K Neuropeptide Y %K Neuropeptides %X Communication between the nervous system and immune system is important for regulating immunity in health and disease. Yu et al. (2022) show that neuropeptide Y and its homolog NPF serve as a "language" to facilitate crosstalk between these two systems across species, enabling neurons to downregulate harmful immune responses. %B Neuron %V 110 %P 1275-1277 %8 2022 Apr 20 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/35447095?dopt=Abstract %R 10.1016/j.neuron.2022.03.036 %0 Journal Article %J Trends Neurosci %D 2022 %T Enteric glial cells mediate gut immunity and repair %A Wallrapp, Antonia %A Yang, Daping %A Chiu, Isaac M %X In the gut, coordinated cell interactions regulate tissue repair and immunity. How enteric glial cells (EGCs) mediate these processes remained elusive. In a recent paper, Progatzky et al. demonstrate that EGCs interact with immune and mesothelial cells under homeostasis and helminth infection, revealing an indispensable role of an interferon-γ (IFNγ)-EGC-CXCL10 axis in tissue repair. %B Trends Neurosci %V 45 %P 251-253 %8 2022 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/34973845?dopt=Abstract %R 10.1016/j.tins.2021.12.001 %0 Journal Article %J Nat Rev Neurosci %D 2022 %T Somatosensory and autonomic neuronal regulation of the immune response %A Udit, Swalpa %A Blake, Kimbria %A Chiu, Isaac M %K Animals %K Humans %K Immune System %K Immunity %K Mammals %K Neuroimmunomodulation %K Neuropeptides %K Peripheral Nervous System %X Bidirectional communication between the peripheral nervous system (PNS) and the immune system is a crucial part of an effective but balanced mammalian response to invading pathogens, tissue damage and inflammatory stimuli. Here, we review how somatosensory and autonomic neurons regulate immune cellular responses at barrier tissues and in peripheral organs. Immune cells express receptors for neuronal mediators, including neuropeptides and neurotransmitters, allowing neurons to influence their function in acute and chronic inflammatory diseases. Distinct subsets of peripheral sensory, sympathetic, parasympathetic and enteric neurons are able to signal to innate and adaptive immune cells to modulate their cellular functions. In this Review, we highlight recent studies defining the molecular mechanisms by which neuroimmune signalling mediates tissue homeostasis and pathology. Understanding the neural circuitry that regulates immune responses can offer novel targets for the treatment of a wide array of diseases. %B Nat Rev Neurosci %V 23 %P 157-171 %8 2022 03 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/34997214?dopt=Abstract %R 10.1038/s41583-021-00555-4 %0 Journal Article %J Nat Neurosci %D 2022 %T Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2+ DRG sensory neurons %A Yang, Nicole J %A Isensee, Jörg %A Neel, Dylan V %A Quadros, Andreza U %A Zhang, Han-Xiong Bear %A Lauzadis, Justas %A Liu, Sai Man %A Shiers, Stephanie %A Belu, Andreea %A Palan, Shilpa %A Marlin, Sandra %A Maignel, Jacquie %A Kennedy-Curran, Angela %A Tong, Victoria S %A Moayeri, Mahtab %A Röderer, Pascal %A Nitzsche, Anja %A Lu, Mike %A Pentelute, Bradley L %A Brüstle, Oliver %A Tripathi, Vineeta %A Foster, Keith A %A Price, Theodore J %A Collier, R John %A Leppla, Stephen H %A Puopolo, Michelino %A Bean, Bruce P %A Cunha, Thiago M %A Hucho, Tim %A Chiu, Isaac M %X Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Nav1.8+ or Advillin+ neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics. %B Nat Neurosci %V 25 %P 168-179 %8 2022 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/34931070?dopt=Abstract %R 10.1038/s41593-021-00973-8 %0 Journal Article %J Nature %D 2022 %T VLDLR and ApoER2 are receptors for multiple alphaviruses %A Clark, Lars E %A Clark, Sarah A %A Lin, ChieYu %A Liu, Jianying %A Adrian Coscia %A Nabel, Katherine G %A Pan Yang %A Neel, Dylan V %A Lee, Hyo %A Vesna Brusic %A Stryapunina, Iryna %A Plante, Kenneth S %A Ahmed, Asim A %A Catteruccia, Flaminia %A Young-Pearse, Tracy L %A Chiu, Isaac M %A Llopis, Paula Montero %A Weaver, Scott C %A Jonathan Abraham %X Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described1-3, most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2-E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD-Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2-E1-mediated infection of human and mouse neurons in culture. The administration of a VLDLR LBD-Fc fusion protein has protective activity against rapidly fatal Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis. %B Nature %V 602 %P 475-480 %8 2022 Feb %G eng %N 7897 %1 http://www.ncbi.nlm.nih.gov/pubmed/34929721?dopt=Abstract %R 10.1038/s41586-021-04326-0 %0 Journal Article %J Front Immunol %D 2021 %T Nociceptive Sensory Neurons Mediate Inflammation Induced by Edema Toxin %A Yang, Nicole J %A Neel, Dylan V %A Deng, Liwen %A Heyang, Michelle %A Kennedy-Curran, Angela %A Tong, Victoria S %A Park, Jin Mo %A Chiu, Isaac M %K Animals %K Anthrax %K Antigens, Bacterial %K Bacillus anthracis %K Bacterial Toxins %K Inflammation %K Mice %K Mice, Inbred C57BL %K Nociceptors %X Bacterial products are able to act on nociceptive neurons during pathogenic infection. Neurogenic inflammation is an active part of pain signaling and has recently been shown to impact host-pathogen defense. Bacillus anthracis Edema Toxin (ET) produces striking edema in peripheral tissues, but the cellular mechanisms involved in tissue swelling are not completely understood. Here, we find that nociceptive neurons play a role in ET-induced edema and inflammation in mice. Subcutaneous footpad infection of B. anthracis Sterne caused ET-dependent local mechanical allodynia, paw swelling and body weight gain. Subcutaneous administration of ET induced paw swelling and vascular leakage, the early phases of which were attenuated in the absence of Trpv1+ or Nav1.8+ nociceptive neurons. Nociceptive neurons express the anthrax toxin receptor ANTXR2, but this did not mediate ET-induced edema. ET induced local cytokine expression and neutrophil recruitment, which were dependent in part on Trpv1+ nociceptive neurons. Ablation of Trpv1+ or Nav1.8+ nociceptive neurons also attenuated early increases in paw swelling and body weight gain during live B. anthracis infection. Our findings indicate that nociceptive neurons play an active role in inflammation caused by B. anthracis and Edema Toxin to potentially influence bacterial pathogenesis. %B Front Immunol %V 12 %P 642373 %8 2021 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/34413846?dopt=Abstract %R 10.3389/fimmu.2021.642373 %0 Journal Article %J PLoS Pathog %D 2021 %T Pseudomonas aeruginosa-induced nociceptor activation increases susceptibility to infection %A Lin, Tiffany %A Quellier, Daisy %A Lamb, Jeffrey %A Voisin, Tiphaine %A Baral, Pankaj %A Bock, Felix %A Schönberg, Alfrun %A Mirchev, Rossen %A Pier, Gerald %A Chiu, Isaac %A Gadjeva, Mihaela %X We report a rapid reduction in blink reflexes during in vivo ocular Pseudomonas aeruginosa infection, which is commonly attributed and indicative of functional neuronal damage. Sensory neurons derived in vitro from trigeminal ganglia (TG) were able to directly respond to P. aeruginosa but reacted significantly less to strains of P. aeruginosa that lacked virulence factors such as pili, flagella, or a type III secretion system. These observations led us to explore the impact of neurons on the host's susceptibility to P. aeruginosa keratitis. Mice were treated with Resiniferatoxin (RTX), a potent activator of Transient Receptor Potential Vanilloid 1 (TRPV1) channels, which significantly ablated corneal sensory neurons, exhibited delayed disease progression that was exemplified with decreased bacterial corneal burdens and altered neutrophil trafficking. Sensitization to disease was due to the increased frequencies of CGRP-induced ICAM-1+ neutrophils in the infected corneas and reduced neutrophil bactericidal activities. These data showed that sensory neurons regulate corneal neutrophil responses in a tissue-specific matter affecting disease progression during P. aeruginosa keratitis. Hence, therapeutic modalities that control nociception could beneficially impact anti-infective therapy. %B PLoS Pathog %V 17 %P e1009557 %8 2021 05 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/33956874?dopt=Abstract %R 10.1371/journal.ppat.1009557 %0 Journal Article %J PLoS Pathog %D 2021 %T Microbes and pain %A Deng, Liwen %A Chiu, Isaac M %B PLoS Pathog %V 17 %P e1009398 %8 2021 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/33793668?dopt=Abstract %R 10.1371/journal.ppat.1009398 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2021 %T The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch %A Voisin, Tiphaine %A Perner, Caroline %A Messou, Marie-Angele %A Shiers, Stephanie %A Ualiyeva, Saltanat %A Kanaoka, Yoshihide %A Price, Theodore J %A Sokol, Caroline L %A Bankova, Lora G %A Austen, K Frank %A Chiu, Isaac M %X Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC, LTD, and LTE, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC and its signaling through the CysLT receptor 2 (CysLTR) in itch. transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected in a broad population of human DRG neurons. Injection of leukotriene C (LTC) or its nonhydrolyzable form NMLTC, but neither LTD nor LTE, induced dose-dependent itch but not pain behaviors in mice. LTC-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC-induced itch was abrogated in mice deficient for or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for , , or mast cells (W mice). CysLTR played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or -induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC acts through CysLTR as its physiological receptor to induce itch, and CysLTR contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch. %B Proc Natl Acad Sci U S A %V 118 %8 2021 Mar 30 %G eng %N 13 %1 http://www.ncbi.nlm.nih.gov/pubmed/33753496?dopt=Abstract %R 10.1073/pnas.2022087118 %0 Journal Article %J Immunity %D 2021 %T Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut %A Yan, Yiqing %A Ramanan, Deepshika %A Rozenberg, Milena %A McGovern, Kelly %A Rastelli, Daniella %A Vijaykumar, Brinda %A Yaghi, Omar %A Voisin, Tiphaine %A Mosaheb, Munir %A Chiu, Isaac %A Itzkovitz, Shalev %A Rao, Meenakshi %A Mathis, Diane %A Benoist, Christophe %X The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3 regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ and Helios subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ proportion. Colonization of germfree mice with commensals, especially RORγ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut. %B Immunity %V 54 %P 499-513.e5 %8 2021 Mar 09 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/33691135?dopt=Abstract %R 10.1016/j.immuni.2021.02.002 %0 Journal Article %J Mucosal Immunol %D 2021 %T The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes %A Jacobson, Amanda %A Yang, Daping %A Vella, Madeleine %A Chiu, Isaac M %X The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases. %B Mucosal Immunol %8 2021 Feb 04 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/33542493?dopt=Abstract %R 10.1038/s41385-020-00368-1 %0 Journal Article %J Nature %D 2021 %T Gut-licensed IFNγ+ NK cells drive LAMP1+ TRAIL+ anti-inflammatory astrocytes %A Sanmarco, Liliana M %A Wheeler, Michael A %A Gutiérrez-Vázquez, Cristina %A Polonio, Carolina Manganeli %A Linnerbauer, Mathias %A Pinho-Ribeiro, Felipe A %A Li, Zhaorong %A Giovannoni, Federico %A Batterman, Katelyn V %A Scalisi, Giulia %A Zandee, Stephanie E J %A Heck, Evelyn S %A Alsuwailm, Moneera %A Rosene, Douglas L %A Becher, Burkhard %A Chiu, Isaac M %A Prat, Alexandre %A Quintana, Francisco J %X Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP1 and the death receptor ligand TRAIL. LAMP1TRAIL astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1TRAIL astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ NK cells that are licensed by the microbiome. %B Nature %V 590 %P 473-479 %8 2021 Feb %G eng %N 7846 %1 http://www.ncbi.nlm.nih.gov/pubmed/33408417?dopt=Abstract %R 10.1038/s41586-020-03116-4 %0 Journal Article %J Neurobiol Pain %D 2020 %T Mechanisms of microbial–neuronal interactions in pain and nociception %A Lagomarsino, Valentina N %A Kostic, Aleksandar D %A Chiu, Isaac M %X Nociceptor sensory neurons innervate barrier tissues that are constantly exposed to microbial stimuli. During infection, pathogenic microorganisms can breach barrier surfaces and produce pain by directly activating nociceptors. Microorganisms that live in symbiotic relationships with their hosts, commensals and mutualists, have also been associated with pain, but the molecular mechanisms of how symbionts act on nociceptor neurons to modulate pain remain largely unknown. In this review, we will discuss the known molecular mechanisms of how microbes directly interact with sensory afferent neurons affecting nociception in the gut, skin and lungs. We will touch on how bacterial, viral and fungal pathogens signal to the host to inflict or suppress pain. We will also discuss recent studies examining how gut symbionts affect pain. Specifically, we will discuss how gut symbionts may interact with sensory afferent neurons either directly, through secretion of metabolites or neurotransmitters, or indirectly,through first signaling to epithelial cells or immune cells, to regulate visceral, neuropathic and inflammatory pain. While this area of research is still in its infancy, more mechanistic studies to examine microbial-sensory neuron crosstalk in nociception may allow us to develop new therapies for the treatment of acute and chronic pain. %B Neurobiol Pain %V 9 %P 100056-100056 %G eng %0 Journal Article %J Immunity %D 2020 %T Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens %A Perner, Caroline %A Flayer, Cameron H %A Zhu, Xueping %A Aderhold, Pamela A %A Dewan, Zaynah N A %A Voisin, Tiphaine %A Camire, Ryan B %A Chow, Ohn A %A Chiu, Isaac M %A Sokol, Caroline L %X

Dendritic cells (DCs) of the cDC2 lineage initiate allergic immunity and in the dermis are marked by their expression of CD301b. CD301b+ dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b+ DCs to the draining lymph node (dLN). Using a model of cutaneous allergen exposure, we show that allergens directly activated TRPV1+ sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons released the neuropeptide Substance P, which stimulated proximally located CD301b+ DCs through the Mas-related G-protein coupled receptor member A1 (MRGPRA1). Substance P induced CD301b+ DC migration to the dLN where they initiated T helper-2 cell differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of an allergic immune response.

%B Immunity %V 53 %P 1063-1077 %G eng %N 5 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2020 %T Transcriptional and proteomic insights into the host response in fatal COVID-19 cases %A Wu, Meng %A Chen, Yaobing %A Xia, Han %A Wang, Changli %A Tan, Chin Yee %A Cai, Xunhui %A Liu, Yufeng %A Ji, Fenghu %A Xiong, Peng %A Liu, Ran %A Guan, Yuanlin %A Duan, Yaqi %A Kuang, Dong %A Xu, Sanpeng %A Cai, Hanghang %A Xia, Qin %A Yang, Dehua %A Wang, Ming-Wei %A Chiu, Isaac M %A Cheng, Chao %A Ahern, Philip P %A Liu, Liang %A Wang, Guoping %A Surana, Neeraj K %A Xia, Tian %A Kasper, Dennis L %X

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

%B Proc Natl Acad Sci U S A %V 117 %P 28336-28343 %G eng %N 45 %0 Journal Article %J Am J Physiol Gastrointest Liver Physiol %D 2020 %T Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel %A van Thiel, Isabelle A. M. %A de Jonge, Wouter J. %A Chiu, Isaac M %A van den Wijngaard, Rene M. %X

Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal disten- sion, frequently prompts episodes of debilitating abdominal pain in irritable bowel syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuroimmune cross talk mecha- nisms in visceral hypersensitivity, working toward understanding how gut micro- biota-neuroimmune cross talk contributes to visceral pain sensation in IBS patients.

%B Am J Physiol Gastrointest Liver Physiol %V 318 %P G1034-G1041 %G eng %N 6 %0 Journal Article %J Curr Opin Neurobiol %D 2020 %T Editorial overview: Brain, gut and immune system interactions %A Chiu, Isaac M %A Rolls, Asya %B Curr Opin Neurobiol %V 62 %P iii-v %G eng %0 Journal Article %J Immunity %D 2020 %T Neuro-immune Interactions in the Tissues %A Chu, Coco %A Artis, David %A Chiu, Isaac M %X The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease. %B Immunity %V 52 %P 464-474 %G eng %N 3 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2020 %T Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle %A Wang, Kathy %A Yaghi, Omar K %A Spallanzani, Raul German %A Chen, Xi %A Zemmour, David %A Lai, Nicole %A Chiu, Isaac M %A Benoist, Christophe %A Mathis, Diane %X

A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33+ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.

%B Proc Natl Acad Sci U S A %V 117 %P 5402-5408 %G eng %N 10 %0 Journal Article %J Nature %D 2020 %T Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells %A Zhang, Bing %A Sai Ma %A Inbal Rachmin %A Megan He %A Baral, Pankaj %A Sekyu Choi %A Gonçalves, William A %A Shwartz, Yulia %A Fast, Eva M %A Yiqun Su %A Zon, Leonard I %A Regev, Aviv %A Buenrostro, Jason D %A Cunha, Thiago M %A Chiu, Isaac M %A Fisher, David E %A Ya-Chieh Hsu %X

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics3,4, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.

%B Nature %V 577 %P 676-681 %G eng %N 7792 %0 Journal Article %J Cell %D 2020 %T Gut-Innervating Nociceptor Neurons Regulate Peyer's Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense %A Lai, Nicole Y %A Musser, Melissa A %A Pinho-Ribeiro, Felipe A %A Baral, Pankaj %A Jacobson, Amanda %A Ma, Pingchuan %A Potts, David E %A Chen, Zuojia %A Paik, Donggi %A Soualhi, Salima %A Yan, Yiqing %A Misra, Aditya %A Goldstein, Kaitlin %A Lagomarsino, Valentina N %A Nordstrom, Anja %A Sivanathan, Kisha N %A Wallrapp, Antonia %A Kuchroo, Vijay K %A Nowarski, Roni %A Starnbach, Michael N %A Shi, Hailian %A Surana, Neeraj K %A An, Dingding %A Wu, Chuan %A Huh, Jun R %A Rao, Meenakshi %A Chiu, Isaac M %X

 

Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.

%B Cell %V 180 %P 33-49.e22 %8 2020 Jan 09 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/31813624?dopt=Abstract %R 10.1016/j.cell.2019.11.014 %0 Journal Article %J Cell Res %D 2019 %T Nociceptor nerves set the stage for skin immunity %A Pinho-Ribeiro, Felipe A %A Chiu, Isaac M %B Cell Res %V 29 %P 877-878 %8 2019 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/31619764?dopt=Abstract %R 10.1038/s41422-019-0240-x %0 Journal Article %J Immunity %D 2019 %T Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses %A Wallrapp, Antonia %A Burkett, Patrick R %A Riesenfeld, Samantha J %A Kim, Se-Jin %A Christian, Elena %A Abdulnour, Raja-Elie E %A Thakore, Pratiksha I %A Schnell, Alexandra %A Lambden, Conner %A Herbst, Rebecca H %A Khan, Pavana %A Tsujikawa, Kazutake %A Xavier, Ramnik J %A Chiu, Isaac M %A Levy, Bruce D %A Regev, Aviv %A Kuchroo, Vijay K %X Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo. %B Immunity %V 51 %P 709-723.e6 %8 2019 10 15 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/31604686?dopt=Abstract %R 10.1016/j.immuni.2019.09.005 %0 Journal Article %J Trends Neurosci %D 2019 %T Neuronal Regulation of Immunity in the Skin and Lungs %A Blake, Kimbria J %A Jiang, Xin Ru %A Chiu, Isaac M %X The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma. %B Trends Neurosci %V 42 %P 537-551 %8 2019 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/31213389?dopt=Abstract %R 10.1016/j.tins.2019.05.005 %0 Journal Article %J Nat Rev Immunol %D 2019 %T Pain and immunity: implications for host defence %A Baral, Pankaj %A Udit, Swalpa %A Chiu, Isaac M %X Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron-immune interactions enhance host protection from infection, but for other pathogens, neuron-immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain. %B Nat Rev Immunol %V 19 %P 433-447 %8 2019 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/30874629?dopt=Abstract %R 10.1038/s41577-019-0147-2 %0 Journal Article %J Immunity %D 2019 %T Mast Cells Get on Your Nerves in Itch %A Voisin, Tiphaine %A Chiu, Isaac M %K Cell Communication %K Humans %K Inflammation %K Mast Cells %K Receptors, G-Protein-Coupled %K Receptors, IgE %X Mast-cell-nerve interactions play an integral role in itch and inflammation. Meixiong et al. (2019) show that the receptors MRGPRB2 and FcεRI mediate distinct types of mast cell activation and nerve interactions and that mast cell activation through MRGPRB2 drives itch in allergic contact dermatitis. %B Immunity %V 50 %P 1117-1119 %8 2019 05 21 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/31117004?dopt=Abstract %R 10.1016/j.immuni.2019.04.007 %0 Journal Article %J Immunity %D 2019 %T Mechanical Skin Injury Promotes Food Anaphylaxis by Driving Intestinal Mast Cell Expansion %A Leyva-Castillo, Juan-Manuel %A Galand, Claire %A Kam, Christy %A Burton, Oliver %A Gurish, Michael %A Musser, Melissa A %A Goldsmith, Jeffrey D %A Hait, Elizabeth %A Nurko, Samuel %A Brombacher, Frank %A Dong, Chen %A Finkelman, Fred D %A Lee, Richard T %A Ziegler, Steven %A Chiu, Isaac %A Austen, K Frank %A Geha, Raif S %K Adolescent %K Anaphylaxis %K Animals %K Cell Proliferation %K Child %K Child, Preschool %K Dermatitis, Atopic %K Female %K Food Hypersensitivity %K Humans %K Immunoglobulin E %K Interleukin-13 %K Interleukin-33 %K Interleukin-4 %K Interleukins %K Intestinal Mucosa %K Lymphocytes %K Male %K Mast Cells %K Mice %K Mice, Inbred BALB C %K Mice, Inbred C57BL %K Signal Transduction %K Skin %X Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs. %B Immunity %V 50 %P 1262-1275.e4 %8 2019 05 21 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/31027995?dopt=Abstract %R 10.1016/j.immuni.2019.03.023 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2018 %T Molecular link between itch and atopic dermatitis %A Voisin, Tiphaine %A Chiu, Isaac M %K Dermatitis, Atopic %K Humans %K Mast Cells %K Membrane Proteins %K Musculoskeletal System %K Pruritus %K Surveys and Questionnaires %B Proc Natl Acad Sci U S A %V 115 %P 12851-12853 %8 2018 12 18 %G eng %N 51 %1 http://www.ncbi.nlm.nih.gov/pubmed/30538205?dopt=Abstract %R 10.1073/pnas.1818879115 %0 Journal Article %J Cell %D 2018 %T Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection %A Pinho-Ribeiro, Felipe A %A Baddal, Buket %A Haarsma, Rianne %A O'Seaghdha, Maghnus %A Yang, Nicole J %A Blake, Kimbria J %A Portley, Makayla %A Verri, Waldiceu A %A Dale, James B %A Wessels, Michael R %A Chiu, Isaac M %K Animals %K Bacterial Proteins %K Botulinum Toxins, Type A %K Calcitonin Gene-Related Peptide %K Caspase 1 %K Diterpenes %K Fasciitis, Necrotizing %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Neurons %K Neutrophils %K Pain %K Signal Transduction %K Skin %K Streptococcal Infections %K Streptococcus pyogenes %K Streptolysins %K TRPV Cation Channels %X The nervous system, the immune system, and microbial pathogens interact closely at barrier tissues. Here, we find that a bacterial pathogen, Streptococcus pyogenes, hijacks pain and neuronal regulation of the immune response to promote bacterial survival. Necrotizing fasciitis is a life-threatening soft tissue infection in which "pain is out of proportion" to early physical manifestations. We find that S. pyogenes, the leading cause of necrotizing fasciitis, secretes streptolysin S (SLS) to directly activate nociceptor neurons and produce pain during infection. Nociceptors, in turn, release the neuropeptide calcitonin gene-related peptide (CGRP) into infected tissues, which inhibits the recruitment of neutrophils and opsonophagocytic killing of S. pyogenes. Botulinum neurotoxin A and CGRP antagonism block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection. We conclude that targeting the peripheral nervous system and blocking neuro-immune communication is a promising strategy to treat highly invasive bacterial infections. VIDEO ABSTRACT. %B Cell %V 173 %P 1083-1097.e22 %8 2018 05 17 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/29754819?dopt=Abstract %R 10.1016/j.cell.2018.04.006 %0 Journal Article %J Nat Med %D 2018 %T Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia %A Baral, Pankaj %A Umans, Benjamin D %A Li, Lu %A Wallrapp, Antonia %A Bist, Meghna %A Kirschbaum, Talia %A Wei, Yibing %A Zhou, Yan %A Kuchroo, Vijay K %A Burkett, Patrick R %A Yipp, Bryan G %A Liberles, Stephen D %A Chiu, Isaac M %K Animals %K Bacterial Infections %K Calcitonin Gene-Related Peptide %K Cytokines %K Female %K Host-Pathogen Interactions %K Male %K Mice, Inbred C57BL %K NAV1.8 Voltage-Gated Sodium Channel %K Neutrophils %K Nociceptors %K Pneumonia %K Receptors, Antigen, T-Cell, gamma-delta %K Sensory Receptor Cells %K Staphylococcal Infections %K Staphylococcus aureus %K T-Lymphocytes %K TRPV Cation Channels %K Vagus Nerve %X Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1 nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1 afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia. %B Nat Med %V 24 %P 417-426 %8 2018 05 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29505031?dopt=Abstract %R 10.1038/nm.4501 %0 Journal Article %J Am J Transplant %D 2018 %T Neuro-immune interactions in inflammation and host defense: Implications for transplantation %A Chavan, Sangeeta S %A Ma, Pingchuan %A Chiu, Isaac M %K Animals %K Diet %K Gastrointestinal Microbiome %K Gastrointestinal Tract %K Graft Rejection %K Humans %K Immune System %K Nervous System %K Organ Transplantation %X Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine. %B Am J Transplant %V 18 %P 556-563 %8 2018 03 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28941325?dopt=Abstract %R 10.1111/ajt.14515 %0 Journal Article %J Neurosci Bull %D 2018 %T Infection, Pain, and Itch %A Chiu, Isaac M %K Animals %K Humans %K Infections %K Neurons %K Pain %K Pruritus %X Pain and itch are unpleasant sensations that often accompany infections caused by viral, bacterial, parasitic, and fungal pathogens. Recent studies show that sensory neurons are able to directly detect pathogens to mediate pain and itch. Nociceptor and pruriceptor neurons respond to pathogen-associated molecular patterns, including Toll-like receptor ligands, N-formyl peptides, and bacterial toxins. Other pathogens are able to silence neuronal activity to produce analgesia during infection. Pain and itch could lead to neuronal modulation of the immune system or behavioral avoidance of future pathogen exposure. Conversely, pathogens could modulate neuronal signaling to potentiate their pathogenesis and facilitate their spread to other hosts. Defining how pathogens modulate pain and itch has critical implications for sensory neurobiology and our understanding of host-microbe interactions. %B Neurosci Bull %V 34 %P 109-119 %8 2018 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28144843?dopt=Abstract %R 10.1007/s12264-017-0098-1 %0 Journal Article %J Nat Commun %D 2018 %T Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314 %A Blake, Kimbria J %A Baral, Pankaj %A Voisin, Tiphaine %A Lubkin, Ashira %A Pinho-Ribeiro, Felipe Almeida %A Adams, Kelsey L %A Roberson, David P %A Ma, Yuxin C %A Otto, Michael %A Woolf, Clifford J %A Torres, Victor J %A Chiu, Isaac M %K Anesthetics, Local %K Animals %K Bacterial Toxins %K Gene Knockdown Techniques %K Lidocaine %K Methicillin-Resistant Staphylococcus aureus %K Mice %K Mice, Inbred C57BL %K Neurons %K Pain %K Staphylococcal Infections %K TRPV Cation Channels %X The hallmark of many bacterial infections is pain. The underlying mechanisms of pain during live pathogen invasion are not well understood. Here, we elucidate key molecular mechanisms of pain produced during live methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that spontaneous pain is dependent on the virulence determinant agr and bacterial pore-forming toxins (PFTs). The cation channel, TRPV1, mediated heat hyperalgesia as a distinct pain modality. Three classes of PFTs-alpha-hemolysin (Hla), phenol-soluble modulins (PSMs), and the leukocidin HlgAB-directly induced neuronal firing and produced spontaneous pain. From these mechanisms, we hypothesized that pores formed in neurons would allow entry of the membrane-impermeable sodium channel blocker QX-314 into nociceptors to silence pain during infection. QX-314 induced immediate and long-lasting blockade of pain caused by MRSA infection, significantly more than lidocaine or ibuprofen, two widely used clinical analgesic treatments. %B Nat Commun %V 9 %P 37 %8 2018 01 02 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29295977?dopt=Abstract %R 10.1038/s41467-017-02448-6 %0 Journal Article %J Nature %D 2017 %T The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation %A Wallrapp, Antonia %A Riesenfeld, Samantha J %A Burkett, Patrick R %A Abdulnour, Raja-Elie E %A Nyman, Jackson %A Dionne, Danielle %A Hofree, Matan %A Cuoco, Michael S %A Rodman, Christopher %A Farouq, Daneyal %A Haas, Brian J %A Tickle, Timothy L %A Trombetta, John J %A Baral, Pankaj %A Klose, Christoph S N %A Mahlakõiv, Tanel %A Artis, David %A Rozenblatt-Rosen, Orit %A Chiu, Isaac M %A Levy, Bruce D %A Kowalczyk, Monika S %A Regev, Aviv %A Kuchroo, Vijay K %K Animals %K Female %K Gene Expression Regulation %K Hypersensitivity %K Immunity, Innate %K Inflammation %K Interleukin-17 %K Interleukin-33 %K Ligands %K Lung %K Lymphocytes %K Male %K Mice %K Mice, Inbred C57BL %K Neuropeptides %K Receptors, Neurotransmitter %K Respiratory Mucosa %K Signal Transduction %K Transcription, Genetic %X Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces. %B Nature %V 549 %P 351-356 %8 2017 09 21 %G eng %N 7672 %1 http://www.ncbi.nlm.nih.gov/pubmed/28902842?dopt=Abstract %R 10.1038/nature24029 %0 Journal Article %J J Intern Med %D 2017 %T Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence %A Lai, Nicole Y %A Blake, Kimbria J %A Chiu, Isaac M %K Bacterial Physiological Phenomena %K Gastroenteritis %K Gastrointestinal Tract %K Humans %K Ion Channels %K Neuropeptides %K Sensory Receptor Cells %X Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases. %B J Intern Med %V 282 %P 5-23 %8 2017 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28155242?dopt=Abstract %R 10.1111/joim.12591 %0 Journal Article %J Int Immunol %D 2017 %T Neuro-immune interactions in allergic diseases: novel targets for therapeutics %A Voisin, Tiphaine %A Bouvier, Amélie %A Chiu, Isaac M %K Animals %K Humans %K Hypersensitivity %K Inflammation %K Molecular Targeted Therapy %K Mucous Membrane %K Nervous System %K Neuroimmunomodulation %K Neuropeptides %K Receptor Cross-Talk %X Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases. %B Int Immunol %V 29 %P 247-261 %8 2017 06 01 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/28814067?dopt=Abstract %R 10.1093/intimm/dxx040 %0 Journal Article %J J Mol Biol %D 2017 %T Bacterial Signaling to the Nervous System through Toxins and Metabolites %A Yang, Nicole J %A Chiu, Isaac M %K Animals %K Bacteroides fragilis %K Brain %K Caenorhabditis elegans %K Central Nervous System %K Clostridium perfringens %K Gastrointestinal Tract %K Humans %K Lipopolysaccharides %K Macrolides %K Mycobacterium ulcerans %K Neurons %K Signal Transduction %K Staphylococcus aureus %K Synaptic Transmission %K Tetanus Toxin %X Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons-olfactory chemosensory neurons and nociceptor sensory neurons-detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the "gut-brain axis" to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases. %B J Mol Biol %V 429 %P 587-605 %8 2017 03 10 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/28065740?dopt=Abstract %R 10.1016/j.jmb.2016.12.023 %0 Journal Article %J Cell %D 2017 %T An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk %A Yissachar, Nissan %A Zhou, Yan %A Ung, Lloyd %A Lai, Nicole Y %A Mohan, James F %A Ehrlicher, Allen %A Weitz, David A %A Kasper, Dennis L %A Chiu, Isaac M %A Mathis, Diane %A Benoist, Christophe %K Animals %K Clostridium %K Intestines %K Mice %K Organ Culture Techniques %K Symbiosis %X Investigation of host-environment interactions in the gut would benefit from a culture system that maintained tissue architecture yet allowed tight experimental control. We devised a microfabricated organ culture system that viably preserves the normal multicellular composition of the mouse intestine, with luminal flow to control perturbations (e.g., microbes, drugs). It enables studying short-term responses of diverse gut components (immune, neuronal, etc.). We focused on the early response to bacteria that induce either Th17 or RORg T-regulatory (Treg) cells in vivo. Transcriptional responses partially reproduced in vivo signatures, but these microbes elicited diametrically opposite changes in expression of a neuronal-specific gene set, notably nociceptive neuropeptides. We demonstrated activation of sensory neurons by microbes, correlating with RORg Treg induction. Colonic RORg Treg frequencies increased in mice lacking TAC1 neuropeptide precursor and decreased in capsaicin-diet fed mice. Thus, differential engagement of the enteric nervous system may partake in bifurcating pro- or anti-inflammatory responses to microbes. %B Cell %V 168 %P 1135-1148.e12 %8 2017 03 09 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/28262351?dopt=Abstract %R 10.1016/j.cell.2017.02.009 %0 Journal Article %J Trends Immunol %D 2017 %T Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation %A Pinho-Ribeiro, Felipe A %A Verri, Waldiceu A %A Chiu, Isaac M %K Adaptive Immunity %K Animals %K Humans %K Immune System %K Immunity, Innate %K Inflammation %K Neuroimmunomodulation %K Neuropeptides %K Neurotransmitter Agents %K Nociceptors %K Pain %K Sensory Receptor Cells %X Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases. %B Trends Immunol %V 38 %P 5-19 %8 2017 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27793571?dopt=Abstract %R 10.1016/j.it.2016.10.001 %0 Journal Article %J Pain %D 2016 %T Pain and infection: pathogen detection by nociceptors %A Chiu, Isaac M %A Pinho-Ribeiro, Felipe A %A Woolf, Clifford J %K Animals %K Humans %K Infections %K Nociceptors %K Pain %B Pain %V 157 %P 1192-3 %8 2016 06 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/27183444?dopt=Abstract %R 10.1097/j.pain.0000000000000559 %0 Journal Article %J Cell Host Microbe %D 2016 %T Pain and Itch: Beneficial or Harmful to Antimicrobial Defense? %A Baral, Pankaj %A Mills, Kimbria %A Pinho-Ribeiro, Felipe A %A Chiu, Isaac M %K Adaptive Immunity %K Host-Pathogen Interactions %K Humans %K Immunity, Innate %K Infections %K Neural Pathways %K Neuroimmunomodulation %K Pain %K Pruritus %K Sensory Receptor Cells %X Pain and itch are unpleasant sensations accompanying many microbial infections. Recent studies demonstrate that pain- and itch-mediating somatosensory neurons are able to directly detect pathogens, triggering neuronal activation and subsequent regulation of immune responses. We discuss whether pain and/or itch during infection is beneficial or harmful to host antimicrobial defense. %B Cell Host Microbe %V 19 %P 755-9 %8 2016 Jun 08 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/27281567?dopt=Abstract %R 10.1016/j.chom.2016.05.010 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2015 %T CD11b+Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity %A Ghasemlou, Nader %A Chiu, Isaac M %A Julien, Jean-Pierre %A Woolf, Clifford J %K Animals %K Antigens, Ly %K CD11b Antigen %K Chemokines %K Cytokines %K Freund's Adjuvant %K Inflammation %K Male %K Mice %K Mice, Inbred C57BL %K Myeloid Cells %K Neutrophils %K Pain %X Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant- and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G(+)CD11b(+) neutrophils and T-cell receptor (TCR) β(+) T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b(+)Ly6G(-) myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2(+)Ly6C(hi)) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b(+)Ly6G(-) myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation. %B Proc Natl Acad Sci U S A %V 112 %P E6808-17 %8 2015 Dec 08 %G eng %N 49 %1 http://www.ncbi.nlm.nih.gov/pubmed/26598697?dopt=Abstract %R 10.1073/pnas.1501372112 %0 Journal Article %J Neuron %D 2015 %T Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation %A Talbot, Sébastien %A Abdulnour, Raja-Elie E %A Burkett, Patrick R %A Lee, Seungkyu %A Cronin, Shane J F %A Pascal, Maud A %A Laedermann, Cedric %A Foster, Simmie L %A Tran, Johnathan V %A Lai, Nicole %A Chiu, Isaac M %A Ghasemlou, Nader %A DiBiase, Matthew %A Roberson, David %A Von Hehn, Christian %A Agac, Busranour %A Haworth, Oliver %A Seki, Hiroyuki %A Penninger, Josef M %A Kuchroo, Vijay K %A Bean, Bruce P %A Levy, Bruce D %A Woolf, Clifford J %K Airway Remodeling %K Anesthetics, Local %K Animals %K Animals, Newborn %K Capsaicin %K Cytokines %K Disease Models, Animal %K Freund's Adjuvant %K Green Fluorescent Proteins %K Interleukin-5 %K Lidocaine %K Mice %K Nociceptors %K Ovalbumin %K Respiratory Hypersensitivity %K Time Factors %K Vasoactive Intestinal Peptide %X Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma. %B Neuron %V 87 %P 341-54 %8 2015 Jul 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26119026?dopt=Abstract %R 10.1016/j.neuron.2015.06.007 %0 Journal Article %J Nat Neurosci %D 2015 %T Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts %A Wainger, Brian J %A Buttermore, Elizabeth D %A Oliveira, Julia T %A Mellin, Cassidy %A Lee, Seungkyu %A Saber, Wardiya Afshar %A Wang, Amy J %A Ichida, Justin K %A Chiu, Isaac M %A Barrett, Lee %A Huebner, Eric A %A Bilgin, Canan %A Tsujimoto, Naomi %A Brenneis, Christian %A Kapur, Kush %A Rubin, Lee L %A Eggan, Kevin %A Woolf, Clifford J %K Animals %K Dysautonomia, Familial %K Electrophysiological Phenomena %K Fibroblasts %K Humans %K Inflammation %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Mice, Transgenic %K Models, Neurological %K Nociceptors %K Pain %K Peripheral Nervous System Diseases %K Sensory Receptor Cells %K Transcription Factors %X Reprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes, but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. We identified five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons. These recapitulated the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons, as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibited TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we found that the technique was able to reveal previously unknown aspects of human disease phenotypes in vitro. %B Nat Neurosci %V 18 %P 17-24 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25420066?dopt=Abstract %R 10.1038/nn.3886 %0 Journal Article %J Elife %D 2014 %T Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity %A Chiu, Isaac M %A Barrett, Lee B %A Williams, Erika K %A Strochlic, David E %A Lee, Seungkyu %A Weyer, Andy D %A Lou, Shan %A Bryman, Gregory S %A Roberson, David P %A Ghasemlou, Nader %A Piccoli, Cara %A Ahat, Ezgi %A Wang, Victor %A Cobos, Enrique J %A Stucky, Cheryl L %A Ma, Qiufu %A Liberles, Stephen D %A Woolf, Clifford J %K Animals %K Cell Separation %K Cluster Analysis %K Flow Cytometry %K Ganglia, Spinal %K Gene Expression Profiling %K Mice %K Patch-Clamp Techniques %K Principal Component Analysis %K Sensory Receptor Cells %K Transcription, Genetic %X The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4(+)SNS-Cre/TdTomato(+), 2) IB4(-)SNS-Cre/TdTomato(+), and 3) Parv-Cre/TdTomato(+) cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. %B Elife %V 3 %8 2014 Dec 19 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25525749?dopt=Abstract %R 10.7554/eLife.04660 %0 Journal Article %J Cell Rep %D 2013 %T A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model %A Chiu, Isaac M %A Morimoto, Emiko T A %A Goodarzi, Hani %A Liao, Jennifer T %A O'Keeffe, Sean %A Phatnani, Hemali P %A Muratet, Michael %A Carroll, Michael C %A Levy, Shawn %A Tavazoie, Saeed %A Myers, Richard M %A Maniatis, Tom %K Amyotrophic Lateral Sclerosis %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microglia %K Transcriptome %X Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1(G93A) mouse model of amyotrophic lateral sclerosis (ALS). We found that SOD1(G93A) microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer's disease genes, are concurrently upregulated. Mutant microglia differed from SOD1(WT), lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation. %B Cell Rep %V 4 %P 385-401 %8 2013 Jul 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23850290?dopt=Abstract %R 10.1016/j.celrep.2013.06.018 %0 Journal Article %J Nature %D 2013 %T Bacteria activate sensory neurons that modulate pain and inflammation %A Chiu, Isaac M %A Heesters, Balthasar A %A Ghasemlou, Nader %A Von Hehn, Christian A %A Zhao, Fan %A Tran, Johnathan %A Wainger, Brian %A Strominger, Amanda %A Muralidharan, Sriya %A Horswill, Alexander R %A Bubeck Wardenburg, Juliane %A Hwang, Sun Wook %A Carroll, Michael C %A Woolf, Clifford J %K Action Potentials %K Animals %K Bacterial Load %K Calcium Signaling %K Female %K Hemolysin Proteins %K Host-Pathogen Interactions %K Hot Temperature %K Hyperalgesia %K Immunity, Innate %K Inflammation %K Lymphatic Diseases %K Male %K Mice %K Mice, Inbred C57BL %K Monocytes %K Myeloid Differentiation Factor 88 %K N-Formylmethionine Leucyl-Phenylalanine %K NAV1.8 Voltage-Gated Sodium Channel %K Neutrophils %K Nociceptors %K Pain %K Protein Stability %K Staphylococcal Infections %K Staphylococcus aureus %K Toll-Like Receptor 2 %X Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions. %B Nature %V 501 %P 52-7 %8 2013 Sep 05 %G eng %N 7465 %1 http://www.ncbi.nlm.nih.gov/pubmed/23965627?dopt=Abstract %R 10.1038/nature12479 %0 Journal Article %J Nat Neurosci %D 2012 %T Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology %A Chiu, Isaac M %A Von Hehn, Christian A %A Woolf, Clifford J %K Autonomic Nervous System %K Humans %K Immune System %K Neurogenic Inflammation %K Nociceptors %K Peripheral Nervous System %K Sensory Receptor Cells %X The peripheral nervous and immune systems are traditionally thought of as serving separate functions. The line between them is, however, becoming increasingly blurred by new insights into neurogenic inflammation. Nociceptor neurons possess many of the same molecular recognition pathways for danger as immune cells, and, in response to danger, the peripheral nervous system directly communicates with the immune system, forming an integrated protective mechanism. The dense innervation network of sensory and autonomic fibers in peripheral tissues and high speed of neural transduction allows rapid local and systemic neurogenic modulation of immunity. Peripheral neurons also seem to contribute to immune dysfunction in autoimmune and allergic diseases. Therefore, understanding the coordinated interaction of peripheral neurons with immune cells may advance therapeutic approaches to increase host defense and suppress immunopathology. %B Nat Neurosci %V 15 %P 1063-7 %8 2012 Jul 26 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22837035?dopt=Abstract %R 10.1038/nn.3144 %0 Journal Article %J Cardiovasc Res %D 2010 %T Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction %A Haas, Michael S %A Alicot, Elisabeth M %A Schuerpf, Franziska %A Chiu, Isaac %A Li, Jinan %A Moore, Francis D %A Carroll, Michael C %K Animals %K Antibodies, Monoclonal %K Antibody Specificity %K Collagen %K Disease Models, Animal %K Epitopes %K Homeodomain Proteins %K Humans %K Immunoglobulin M %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Molecular Mimicry %K Monocytes %K Myocardial Infarction %K Myocardial Reperfusion Injury %K Myocardium %K Myosin Heavy Chains %K Neutrophil Infiltration %K Peptides %K Time Factors %K Troponin I %X AIMS: Coronary artery occlusion resulting in ischaemia/reperfusion (I/R) injury is a major cause of mortality in the western world. Circulating natural IgM has been shown to play a significant role in reperfusion injury, leading to the notion of a pathogenic response against self by the innate immune system. A specific self-antigen (non-muscle myosin heavy chain II) was recently identified as the major target of pathogenic natural IgM. Therefore, we hypothesized that a synthetic peptide mimetope (N2) or monoclonal antibodies directed against the self-antigen would prevent specific IgM binding to the self-antigen and reduce reperfusion injury in the heart. METHODS AND RESULTS: We find that treatment with N2 peptide reduces infarct size by 47% and serum cardiac troponin-I levels by 69% following 1 h ischaemia and 24 h reperfusion. N2 peptide or an anti-N2 F(ab')(2) (21G6) is also effective at preventing IgM and complement deposition. Additionally, N2 peptide treatment significantly reduces monocyte and neutrophil infiltration at 24 h and collagen deposition at 5 days. Finally, we show that human IgM (hIgM) also includes specificity for the highly conserved self-antigen and that myocardial injury in antibody-deficient mice reconstituted with hIgM is blocked by treatment with N2 peptide or 21G6 F(ab')(2). CONCLUSION: The findings in this study identify potential therapeutics [i.e. N2 peptide or 21G6 F(ab')(2)] that prevent specific IgM binding to ischaemic antigens in the heart, resulting in a significant reduction in cardiac I/R injury. %B Cardiovasc Res %V 87 %P 618-27 %8 2010 Sep 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20462867?dopt=Abstract %R 10.1093/cvr/cvq141 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2009 %T Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice %A Chiu, Isaac M %A Phatnani, Hemali %A Kuligowski, Michael %A Tapia, Juan C %A Carrasco, Monica A %A Zhang, Ming %A Maniatis, Tom %A Carroll, Michael C %K Aging %K Amyotrophic Lateral Sclerosis %K Animals %K Complement C4 %K Flow Cytometry %K Green Fluorescent Proteins %K Immunity, Humoral %K Immunity, Innate %K Macrophage Activation %K Mice %K Mice, Transgenic %K Muscles %K Mutation %K Myeloid Cells %K Nerve Degeneration %K Peripheral Nervous System %K Phenotype %K Sciatic Nerve %K Spinal Cord %K Staining and Labeling %K Superoxide Dismutase %X During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1(G93A) and SOD1(G37R) transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice. %B Proc Natl Acad Sci U S A %V 106 %P 20960-5 %8 2009 Dec 08 %G eng %N 49 %1 http://www.ncbi.nlm.nih.gov/pubmed/19933335?dopt=Abstract %R 10.1073/pnas.0911405106 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2008 %T T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS %A Chiu, Isaac M %A Chen, Adam %A Zheng, Yi %A Kosaras, Bela %A Tsiftsoglou, Stefanos A %A Vartanian, Timothy K %A Brown, Robert H %A Carroll, Michael C %K Amyotrophic Lateral Sclerosis %K Animals %K CD11c Antigen %K Cell Separation %K Cytoprotection %K Dendritic Cells %K Disease Models, Animal %K Disease Progression %K Gene Expression Profiling %K Humans %K Inflammation %K Insulin-Like Growth Factor I %K Interleukin-4 %K Mice %K Mice, Transgenic %K Microglia %K Mutant Proteins %K Mutation %K Neurons %K Phenotype %K Spinal Cord %K Superoxide Dismutase %K Superoxide Dismutase-1 %K T-Lymphocytes %X Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 (SOD1)(G93A) transgenic mouse model of ALS. CD4+ and CD8+ T cells infiltrated SOD1(G93A) spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRbeta deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1(G93A) (TCRbeta-/-) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury. %B Proc Natl Acad Sci U S A %V 105 %P 17913-8 %8 2008 Nov 18 %G eng %N 46 %1 http://www.ncbi.nlm.nih.gov/pubmed/18997009?dopt=Abstract %R 10.1073/pnas.0804610105 %0 Journal Article %J Biochem Biophys Res Commun %D 2007 %T Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action %A Zhang, Haimou %A Qin, Gangjian %A Liang, Gang %A Li, Jinan %A Chiu, Isaac %A Barrington, Robert A %A Liu, Dongxu %K Cells, Cultured %K Complement C1 Inactivator Proteins %K Complement C1 Inhibitor Protein %K Dose-Response Relationship, Drug %K Endothelial Cells %K Humans %K Lipopolysaccharides %K Serpins %K Vascular Cell Adhesion Molecule-1 %X Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanism of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-kappaB activation and nuclear translocation in an IkappaBalpha-dependent manner. The inhibitory effects were associated with reduction of inhibitor IkappaB kinase activity and stabilization of the NF-kappaB inhibitor IkappaB. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations. %B Biochem Biophys Res Commun %V 358 %P 1120-7 %8 2007 Jul 13 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/17521609?dopt=Abstract %R 10.1016/j.bbrc.2007.05.058 %0 Journal Article %J Biochem Biophys Res Commun %D 2006 %T Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury %A Fu, Jinrong %A Lin, Guosheng %A Wu, Zhiwei %A Ceng, Bin %A Wu, Yanxia %A Liang, Gong %A Qin, Gangjian %A Li, Jinan %A Chiu, Isaac %A Liu, Dongxu %K Animals %K Anti-Inflammatory Agents %K Apoptosis %K Biological Transport %K Cardiotonic Agents %K Caspase 3 %K Caspases %K Complement C1 %K Complement C1 Inhibitor Protein %K Enzyme Activation %K Myocardium %K Peroxidase %K Rats %K Rats, Sprague-Dawley %K Reperfusion Injury %X Complement activation augments myocardial cell injury and apoptosis during ischemia/reperfusion (I/R), whereas complement system inhibition with C1 inhibitor (C1INH), a serine protease inhibitor, exerts markedly cardioprotective effects. Our recent data demonstrate that C1INH prevents vascular endothelial cell apoptosis and a "modified" form of the reactive center loop-cleaved, inactive C1INH (iC1INH) plays an anti-inflammatory role in endotoxin shock. The aim of this study was to determine whether C1INH protects against myocardial cell injury via an anti-apoptotic activity or anti-inflammatory effect. In a rat model of acute myocardial infarction (AMI) induced by I/R, administration of C1INH protected against cardiomyocytic apoptosis via normalization of ratio of the Bcl-2/Bax expression in the myocardial infarct area. C1INH improved parameters of cardiac function and hemodynamics and reduced myocardial infarct size (MIS). In addition, myocardial and blood myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, was decreased by treatment of C1INH. In cultured H9c2 rat cardiomyocytic cells, C1INH blocked hypoxia/reoxygenation-induced apoptosis in the absence of sera associated with inhibition of cytochrome c translocation and suppression of caspase-3 activation. The proportion of Bcl-2/Bax expression induced by hypoxia/reoxygenation was reversed by C1INH. Importantly, iC1INH also revealed these similar effects, indicating that C1INH has a direct anti-apoptotic activity. Therefore, these studies support the hypothesis that C1INH, in addition to inhibition of activation of the complement and contact systems, improves outcome in I/R-mediated myocardial cell injury via an anti-apoptotic activity independent of serine protease inhibitory activity. %B Biochem Biophys Res Commun %V 349 %P 504-12 %8 2006 Oct 20 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/16942749?dopt=Abstract %R 10.1016/j.bbrc.2006.08.065 %0 Journal Article %J J Exp Med %D 2006 %T Identification of the target self-antigens in reperfusion injury %A Zhang, Ming %A Alicot, Elisabeth M %A Chiu, Isaac %A Li, Jinan %A Verna, Nicola %A Vorup-Jensen, Thomas %A Kessler, Benedikt %A Shimaoka, Motomu %A Chan, Rodney %A Friend, Daniel %A Mahmood, Umar %A Weissleder, Ralph %A Moore, Francis D %A Carroll, Michael C %K Animals %K Autoantigens %K Autoimmunity %K Capillary Permeability %K Hindlimb %K Homeodomain Proteins %K Immunity, Innate %K Immunoglobulin M %K Ischemia %K Jejunum %K Mice %K Mice, Inbred C57BL %K Mice, Knockout %K Muscle, Skeletal %K Nonmuscle Myosin Type IIA %K Reperfusion Injury %X Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction. %B J Exp Med %V 203 %P 141-52 %8 2006 Jan 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/16390934?dopt=Abstract %R 10.1084/jem.20050390 %0 Journal Article %J J Cell Biol %D 2006 %T Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis %A Ma, Yinghua %A Li, Jianxue %A Chiu, Isaac %A Wang, Yawen %A Sloane, Jacob A %A Lü, Jining %A Kosaras, Bela %A Sidman, Richard L %A Volpe, Joseph J %A Vartanian, Timothy %K Animals %K Apoptosis %K Blotting, Western %K Cells, Cultured %K Embryo, Mammalian %K Enzyme-Linked Immunosorbent Assay %K Gene Expression Regulation, Developmental %K I-kappa B Kinase %K Immunoenzyme Techniques %K In Situ Hybridization %K Mice %K Neurites %K Neurons %K NF-kappa B %K Signal Transduction %K Toll-Like Receptor 8 %X Toll receptors in Drosophila melanogaster function in morphogenesis and host defense. Mammalian orthologues of Toll, the Toll-like receptors (TLRs), have been studied extensively for their essential functions in controlling innate and adaptive immune responses. We report that TLR8 is dynamically expressed during mouse brain development and localizes to neurons and axons. Agonist stimulation of TLR8 in cultured cortical neurons causes inhibition of neurite outgrowth and induces apoptosis in a dissociable manner. Our evidence indicates that such TLR8-mediated neuronal responses do not involve the canonical TLR-NF-kappaB signaling pathway. These findings reveal novel functions for TLR8 in the mammalian nervous system that are distinct from the classical role of TLRs in immunity. %B J Cell Biol %V 175 %P 209-15 %8 2006 Oct 23 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/17060494?dopt=Abstract %R 10.1083/jcb.200606016 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2004 %T Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury %A Zhang, Ming %A Austen, William G %A Chiu, Isaac %A Alicot, Elisabeth M %A Hung, Rachel %A Ma, Minghe %A Verna, Nicola %A Xu, Min %A Hechtman, Herbert B %A Moore, Francis D %A Carroll, Michael C %K Animals %K B-Lymphocytes %K Homeodomain Proteins %K Hybridomas %K Immunoglobulin M %K Intestines %K Mice %K Mice, Knockout %K Molecular Sequence Data %K Reperfusion Injury %X Reperfusion injury of ischemic tissue represents an acute inflammatory response that can cause significant morbidity and mortality. The mechanism of injury is not fully elucidated, but recent studies indicate an important role for natural antibody and the classical pathway of complement. To test the hypothesis that injury is initiated by specific IgM, we have screened a panel of IgM-producing hybridomas prepared from peritoneal cells enriched in B-1 cells. One clone, CM22, was identified that could restore pathogenic injury in RAG-1(-/-) mice in an intestinal model of ischemia/reperfusion (I/R). In situ activation of the classical pathway of complement was evident by deposition of IgM, complement C4, and C3 in damaged tissue after passive transfer of CM22 IgM. Sequence analysis of CM22 Ig heavy and light chains showed germ-line configurations with high homology to a V(H) sequence from the B-1 repertoire and a V(K) of a known polyreactive natural IgM. These data provide definitive evidence that I/R injury can be initiated by clonally specific natural IgM that activates the classical pathway of complement. This finding opens an avenue for identification of I/R-specific self-antigen(s) and early prevention of injury. %B Proc Natl Acad Sci U S A %V 101 %P 3886-91 %8 2004 Mar 16 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/14999103?dopt=Abstract %R 10.1073/pnas.0400347101 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2004 %T MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression %A Deng, Lih-Wen %A Chiu, Isaac %A Strominger, Jack L %K Animals %K Cell Cycle %K Cell Division %K Cell Line %K Cell Nucleus %K Chromatin %K COS Cells %K DNA-Binding Proteins %K Gene Expression %K HeLa Cells %K Humans %K Jurkat Cells %K Leukemia, Myeloid %K Microscopy, Confocal %K Nuclear Localization Signals %K Recombinant Fusion Proteins %X MLL5 is a mammalian trithorax group (trx-G) gene identified within chromosome band 7q22, a frequently deleted element found in cytogenetic aberrations of acute myeloid malignancies. MLL5 cDNA was linked with the FLAG and V5 tags at the N and C terminus, respectively, and transfected into 293T cells. Immunofluoresence staining of the expressed tagged MLL5 protein showed localization to the nucleus and exclusion from nucleoli, and no surface staining was detected. Both ectopically introduced and endogenous MLL5 protein displayed a speckled nuclear distribution. By using a series of MLL5-truncated mutants fused with enhanced GFP, a domain (residues 945-1,156) required for foci accumulation was identified, and regions containing functional nuclear localization signals were mapped. Ectopic overexpression of GFP-MLL5 induced cell cycle arrest in G(1) phase. This inhibition of cell cycle progression was indicated by delayed progression into nocodazole-induced mitotic arrest and was confirmed by a lack of BrdUrd incorporation. These findings suggest that MLL5 forms intranuclear protein complexes that may play an important role in chromatin remodeling and cellular growth suppression. %B Proc Natl Acad Sci U S A %V 101 %P 757-62 %8 2004 Jan 20 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/14718661?dopt=Abstract %R 10.1073/pnas.2036345100 %0 Journal Article %J Proc Natl Acad Sci U S A %D 1999 %T The human natural killer cell immune synapse %A Daniel M Davis %A Chiu, Isaac M %A Marlys Fassett %A George B Cohen %A Ofer Mandelboim %A Strominger, Jack L %K Actins %K Adenosine Triphosphate %K Cations, Divalent %K Cell Adhesion %K Cytoskeleton %K Cytotoxicity, Immunologic %K Green Fluorescent Proteins %K Histocompatibility Antigens Class I %K HLA-C Antigens %K Humans %K Immunologic Capping %K Killer Cells, Natural %K Luminescent Proteins %K Movement %K Receptors, Immunologic %K Receptors, KIR %K Recombinant Fusion Proteins %K Tubulin %X Inhibitory killer Ig-like receptors (KIR) at the surface of natural killer (NK) cells induced clustering of HLA-C at the contacting surface of target cells. In this manner, inhibitory immune synapses were formed as human NK cells surveyed target cells. At target/NK cell synapses, HLA-C/KIR distributed into rings around central patches of intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, the opposite orientation to mature murine T cell-activating synapses. This organization of protein was stable for at least 20 min. Cells could support multiple synapses simultaneously, and clusters of HLA-C moved as NK cells crawled over target cells. Clustering required a divalent metal cation, explaining how metal chelators inhibit KIR function. Surprisingly, however, formation of inhibitory synapses was unaffected by ATP depletion and the cytoskeletal inhibitors, colchicine and cytochalsins B and D. Clearly, supramolecular organization within plasma membranes is critical for NK cell immunosurveillance. %B Proc Natl Acad Sci U S A %V 96 %P 15062-7 %8 1999 Dec 21 %G eng %N 26 %1 http://www.ncbi.nlm.nih.gov/pubmed/10611338?dopt=Abstract %R 10.1073/pnas.96.26.15062 %0 Journal Article %J Proc Natl Acad Sci U S A %D 1999 %T Trafficking of spontaneously endocytosed MHC proteins %A Chiu, Isaac M %A Daniel M Davis %A Strominger, Jack L %K B-Lymphocytes %K beta 2-Microglobulin %K Binding Sites %K Cell Compartmentation %K Cell Line %K Cell Membrane %K Endocytosis %K Endosomes %K Enterotoxins %K Fluorescent Dyes %K Green Fluorescent Proteins %K Histocompatibility Antigens Class I %K Histocompatibility Antigens Class II %K HLA-C Antigens %K Humans %K Intracellular Fluid %K Luminescent Proteins %K Xanthenes %X Class I MHC protein primarily presents endogenous antigen but also may present exogenous antigen. Here, we investigated the intracellular pathway of spontaneously internalized class I MHC protein by confocal microscopy. beta(2)-microglobulin (beta(2)m), labeled with a single fluorophore, was exchanged at the surface of B cell transfectants to specifically mark cell surface and endocytosed class I MHC protein. Intracellular beta(2)m colocalized with fluorophore-conjugated transferrin, implying that class I MHC protein endocytosed into early endosomes. These endosomes containing fluorescent beta(2)m were found close to or within the Golgi apparatus, marked by fluorescent ceramide. Even after 24 hr of incubation, very little fluorescent beta(2)m was found in intracellular organelles stained by DiOC(6), marking the endoplasmic reticulum, or fluorophore-conjugated low density lipoprotein, marking late endosomes and lysosomes. Fluorophore-conjugated superantigens (staphylococcal enterotoxin A and B), presumed to enter cells bound to class II MHC protein, also were found to endocytose into beta(2)m-containing early endosomes. Staining with mAb and use of transfectants expressing MHC protein attached to green fluorescent protein confirmed the presence of intracellular compartments rich in both class I and II MHC protein and demonstrated that class I and II MHC protein also colocalize in discrete microdomains at the cell surface. These cell surface microdomains also contained transferrin receptor and often were juxtaposed to cholesterol-rich lipid rafts. Thus, class I and II MHC protein meet in microdomains of the plasma membrane and endocytose into early endosomes, where both may acquire and present exogenous antigen. %B Proc Natl Acad Sci U S A %V 96 %P 13944-9 %8 1999 Nov 23 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/10570178?dopt=Abstract %R 10.1073/pnas.96.24.13944 %0 Journal Article %J Eur J Immunol %D 1997 %T Impaired spontaneous endocytosis of HLA-G %A Daniel M Davis %A Hugh T Reyburn %A Laszlo Pazmany %A Chiu, Isaac M %A Ofer Mandelboim %A Strominger, Jack L %K B-Lymphocytes %K beta 2-Microglobulin %K Endocytosis %K Flow Cytometry %K Fluorescent Dyes %K Histocompatibility Antigens Class I %K HLA Antigens %K HLA-C Antigens %K HLA-G Antigens %K Humans %K Microscopy, Confocal %K Microscopy, Fluorescence %K Point Mutation %K Recombinant Fusion Proteins %K Structure-Activity Relationship %K Transfection %K Trophoblasts %K Xanthenes %X HLA-G is a class Ib (non-classical) major histocompatibility complex (MHC) protein expressed at the maternal-fetal interface that inhibits natural killer (NK) cell-mediated lysis in an allotype-independent manner. Here we report that the spontaneous endocytosis of HLA-G is severely reduced because of its short cytoplasmic tail. Class I (classical) MHC proteins on the surface of B cell transfectants detected by primary and secondary antibodies underwent endocytosis at a moderate rate, whereas HLA-G, chimeric proteins consisting of the extracellular domains of HLA-C with the C-terminal sequence of HLA-G, or glycophosphatidylinositol-tailed HLA-C proteins, were not efficiently internalized. In addition, a mutant of beta 2-microglobulin (Ser88Cys) that could be specifically labeled with Texas red (or other fluorescent probes) and exchanged into class I or class Ib MHC proteins was employed to study spontaneous internalization of MHC proteins by a non-perturbative method independent of an antibody ligand. These data are discussed in terms of both the role of HLA-G expressed on the fetal trophoblast and the function of the cytoplasmic tail in class I MHC proteins. %B Eur J Immunol %V 27 %P 2714-9 %8 1997 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/9368631?dopt=Abstract %R 10.1002/eji.1830271035 %0 Journal Article %J J Educ Psychol %D 1979 %T Anxiety research in educational psychology %A Tobias, S %K Anxiety %K Desensitization, Psychologic %K Humans %K Learning %K Memory %K Models, Psychological %K Relaxation Therapy %K Research Design %K Teaching %B J Educ Psychol %V 47 %P 573-82 %8 1979 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/41010?dopt=Abstract %0 Journal Article %J Eur J Biochem %D 1977 %T The purification and properties of NADP-dependent isocitrate dehydrogenase from ox-heart mitochondria %A Macfarlane, N %A Mathews, B %A Dalziel, K %K Amino Acids %K Animals %K Cattle %K Isocitrate Dehydrogenase %K Kinetics %K Mitochondria, Muscle %K Molecular Weight %K Myocardium %K NADP %K Spectrometry, Fluorescence %K Tryptophan %X The purification of NADP-linked isocitrate dehydrogenase from ox heart mitochondria is described. The molecular weight from gel filtration, sedimentation equilibrium and gel electrophoresis is 90000+/-4000, and there are two subunits in the molecule each of which binds NADPH with enhancement of the coenzyme fluorescence. The amino-acid composition is reported, and the absorption coefficient, A1/280%, estimated from dry weight measurements is 11.8 cm-1. %B Eur J Biochem %V 74 %P 553-9 %8 1977 Apr 15 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/15840?dopt=Abstract %R 10.1111/j.1432-1033.1977.tb11424.x %0 Journal Article %J Sem Hop %D 1976 %T [Comparison of clinical effect and blood concentration of phenylbutazone during long-term treatment] %A Gaucher, A %A Royer, R J %A P. Netter %A Royer-Morrot, M J %A Faure, G %A Pourel, J %K Adult %K Aged %K Arthritis, Rheumatoid %K Female %K Humans %K Male %K Middle Aged %K Phenylbutazone %K Spondylitis, Ankylosing %B Sem Hop %V 52 %P 1723-4 %8 1976 Sep 10-20 %G fre %N 31-32 %1 http://www.ncbi.nlm.nih.gov/pubmed/191919?dopt=Abstract %0 Journal Article %J J Am Chem Soc %D 1976 %T Letter: Protostreptovaricins I-V %A Deshmukh, P V %A Kakinuma, K %A Ameel, J J %A Rinehart, K L %A Wiley, P F %A Li, L H %K Chemical Phenomena %K Chemistry %K Chromatography %K Magnetic Resonance Spectroscopy %K Streptovaricin %B J Am Chem Soc %V 98 %P 870-2 %8 1976 Feb 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/1440?dopt=Abstract %R 10.1021/ja00419a056 %0 Journal Article %J J Embryol Exp Morphol %D 1976 %T Properties and development of erythropoietic stem cells in the chick embryo %A Samarut, J %A Nigon, V %K Age Factors %K Animals %K Blood Cell Count %K Bone Marrow %K Chick Embryo %K Erythrocyte Count %K Erythrocytes %K Female %K Hematopoietic Stem Cell Transplantation %K Hematopoietic Stem Cells %K Tibia %K Transplantation, Heterologous %K Vitelline Membrane %X 1. When injected into irradiated chickens, haemopoietic stem cells give rise to well-defined erythrocytic colonies in the host marrow. Such stem cells (CFU-M = Colony Forming Unit in Marrow) have been found in different tissue of the chicke embryo (yolk sac, blood, marrow). Analysis of the properties of CFU-M reveals that they represent two classes of stem cells: pluripotent stem cells mainly in adult marrow and erythrocytic-committed stem cells present in yolk sac. 2. Yolk sac contains the main pool of CFU-M during the major part of embryonic life. In the blood of 6-day-old embryo, there are three or four times more CFU-Ms than in the yolk sac; they are no longer detected in the blood after the 16th day of incubation. During development of the marrow, stem cells are actively differentiating and their total number remains the same from 16 days to hatching. %B J Embryol Exp Morphol %V 36 %P 247-60 %8 1976 Oct %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/12240?dopt=Abstract %0 Journal Article %J Biochim Biophys Acta %D 1975 %T Bile acids. XLVII. 12alpha-Hydroxylation of precursors of allo bile acids by rabbit liver microsomes %A Ali, S S %A Elliott, W H %K Aging %K Animals %K Bile Acids and Salts %K Female %K Kinetics %K Male %K Microsomes, Liver %K Mixed Function Oxygenases %K NADP %K Oxidation-Reduction %K Rabbits %K Sex Factors %X Rabbit liver microsomal preparations fortified with 0.1 mM NADPH effectively promote hydroxylation of [3beta-3H]- or [24-14C]allochenodeoxycholic acid or [5alpha,6alpha-3H2]5alpha-cholestane-3alpha,7alpha-diol to their respective 12alpha-hydroxyl derivatives in yields of about 25 or 65% in 60 min. Minor amounts of other products are formed from the diol. The requirements for activity of rabbit liver microsomal 12alpha-hydroxylase resemble those of rat liver microsomes. Of a number of enzyme inhibitors studied only p-chloromercuribenzoate demonstrated a marked ability to inhibit the reaction with either tritiated substrate. There was no difference in the quantity of product produced from the tritiated acid or the 14C-labeled acid. No clear sex difference was found in activity of the enzyme, nor was an appreciable difference noted in activity of the enzyme between mature and immature animals. %B Biochim Biophys Acta %V 409 %P 249-57 %8 1975 Nov 21 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/65?dopt=Abstract %R 10.1016/0005-2760(75)90159-9 %0 Journal Article %J Biochem Pharmacol %D 1975 %T Comparison between procaine and isocarboxazid metabolism in vitro by a liver microsomal amidase-esterase %A Moroi, K %A Sato, T %K Amidohydrolases %K Animals %K Esterases %K Hydrogen-Ion Concentration %K In Vitro Techniques %K Isocarboxazid %K Kinetics %K Male %K Metals %K Microsomes, Liver %K Phospholipids %K Procaine %K Proteins %K Rats %K Subcellular Fractions %K Temperature %B Biochem Pharmacol %V 24 %P 1517-21 %8 1975 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/8?dopt=Abstract %R 10.1016/0006-2952(75)90029-5 %0 Journal Article %J Biochem Biophys Res Commun %D 1975 %T Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution %A Bose, K S %A Sarma, R H %K Fourier Analysis %K Magnetic Resonance Spectroscopy %K Models, Molecular %K Molecular Conformation %K NAD %K NADP %K Structure-Activity Relationship %K Temperature %B Biochem Biophys Res Commun %V 66 %P 1173-9 %8 1975 Oct 27 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/2?dopt=Abstract %R 10.1016/0006-291x(75)90482-9 %0 Journal Article %J Biochem Pharmacol %D 1975 %T Digitoxin metabolism by rat liver microsomes %A Schmoldt, A %A Benthe, H F %A Haberland, G %K Animals %K Chromatography, Thin Layer %K Digitoxigenin %K Digitoxin %K Hydroxylation %K In Vitro Techniques %K Male %K Microsomes, Liver %K NADP %K Rats %K Time Factors %B Biochem Pharmacol %V 24 %P 1639-41 %8 1975 Sep 01 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/10?dopt=Abstract %0 Journal Article %J Biochem Med %D 1975 %T Formate assay in body fluids: application in methanol poisoning %A Makar, A B %A McMartin, K E %A Palese, M %A Tephly, T R %K Aldehyde Oxidoreductases %K Animals %K Body Fluids %K Carbon Dioxide %K Formates %K Haplorhini %K Humans %K Hydrogen-Ion Concentration %K Kinetics %K Methanol %K Methods %K Pseudomonas %B Biochem Med %V 13 %P 117-26 %8 1975 Jun %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/1?dopt=Abstract %R 10.1016/0006-2944(75)90147-7 %0 Journal Article %J Biochem Pharmacol %D 1975 %T Identification of adenylate cyclase-coupled beta-adrenergic receptors with radiolabeled beta-adrenergic antagonists %A Lefkowitz, R J %K Adenylyl Cyclases %K Adrenergic beta-Antagonists %K Alprenolol %K Animals %K Anura %K Binding Sites %K Catecholamines %K Cattle %K Cell Membrane %K Eels %K Erythrocytes %K Guinea Pigs %K In Vitro Techniques %K Isoproterenol %K Kinetics %K Propranolol %K Receptors, Adrenergic %K Stereoisomerism %K Tritium %B Biochem Pharmacol %V 24 %P 1651-8 %8 1975 Sep 15 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/11?dopt=Abstract %R 10.1016/0006-2952(75)90001-5 %0 Journal Article %J Br J Clin Pract %D 1975 %T Lorazepam in sexual disorders %A Maneksha, S %A Harry, T V %K Adult %K Anti-Anxiety Agents %K Anxiety %K Clinical Trials as Topic %K Female %K Humans %K Lorazepam %K Male %K Placebos %K Psychotherapy %K Sexual Dysfunction, Physiological %B Br J Clin Pract %V 29 %P 175-6 %8 1975 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/29?dopt=Abstract %0 Journal Article %J Biochem Biophys Res Commun %D 1975 %T Metal substitutions incarbonic anhydrase: a halide ion probe study %A Smith, R J %A Bryant, R G %K Animals %K Binding Sites %K Cadmium %K Carbonic Anhydrases %K Cattle %K Humans %K Hydrogen-Ion Concentration %K Magnetic Resonance Spectroscopy %K Mercury %K Protein Binding %K Protein Conformation %K Zinc %B Biochem Biophys Res Commun %V 66 %P 1281-6 %8 1975 Oct 27 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/3?dopt=Abstract %R 10.1016/0006-291x(75)90498-2 %0 Journal Article %J Psychopharmacol Bull %D 1975 %T Possible involvement of GABA in the central actions of benzodiazepines %A Haefely, W %A Kulcsár, A %A Möhler, H %K Aminobutyrates %K Aminooxyacetic Acid %K Animals %K Anti-Anxiety Agents %K Benzodiazepines %K Cats %K gamma-Aminobutyric Acid %K In Vitro Techniques %K Mice %K Neurons %B Psychopharmacol Bull %V 11 %P 58-9 %8 1975 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/720?dopt=Abstract %0 Journal Article %J Acta Virol %D 1975 %T On the problem of oncogene of tumour viruses %A Mekler, L B %K Autoimmune Diseases %K Cell Transformation, Neoplastic %K DNA, Viral %K Genetic Code %K Humans %K Neoplasms %K Oncogenic Viruses %K RNA, Viral %K Transcription, Genetic %K Viral Proteins %K Virus Replication %X The approach to the problem of oncogenesis of tumorigenic viruses is compared and analyzed from the position of the Altshtein-Vogt hypothesis and from that of the general theory of oncogenesis advanced by the present author. In contrast to the hypothesis of Altshtein-Vogt dealing mainly with the problem of oncogene origin, the general theory of oncogenesis not only defines concretely the origin of the oncogene and the essence of its product, but also makes it possible to understand why, when and how integration of the oncogene with the genome of the cell leads to the transformation of the cell into a benign cell and when into a malignant tumour cell. An analysis of the essence of the "oncogene position effect" from this standpoint shows that an integration, similar in its mechanism but differing in polarity, of the genome of other viruses with the cell genome should lead to the formation of a corresponding antiviral stable (life-long) immunity or also to the emergence of pseudoautoimmune disease of the type caused by "slow" viruses. %B Acta Virol %V 19 %P 501-8 %8 1975 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/2001?dopt=Abstract %0 Journal Article %J Br J Haematol %D 1975 %T A serum haemagglutinating property dependent upon polycarboxyl groups %A Beck, M L %A Freihaut, B %A Henry, R %A Pierce, S %A Bayer, W L %K ABO Blood-Group System %K Aged %K Agglutinins %K Antibody Specificity %K Carboxylic Acids %K Cations, Divalent %K Citrates %K Edetic Acid %K Ficain %K Hemagglutination %K Humans %K Hydrogen-Ion Concentration %K Neuraminidase %K Papain %X A serum agglutinin reactive with red cells in the presence of polycarboxyl groups is reported. It is likely that this represents an additional example of the type of agglutinin previously described as agglutinating red cells in the absence of ionized calcium. Experimental evidence is presented indicating that it is free polycarboxyl groups that potentiate agglutination and that any metal ion, such as calcium, capable of chelating with these groups will prove to be inhibitory. %B Br J Haematol %V 29 %P 149-56 %8 1975 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/32?dopt=Abstract %R 10.1111/j.1365-2141.1975.tb01808.x %0 Journal Article %J Acta Virol %D 1975 %T V.I. Gavrilov %K History, 20th Century %K USSR %K Virology %B Acta Virol %V 19 %P 510 %8 1975 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/2003?dopt=Abstract