Isabelle A. M. van Thiel, Wouter J. de Jonge, Isaac M Chiu, and Rene M. van den Wijngaard. 6/1/2020. “Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel.” Am J Physiol Gastrointest Liver Physiol, 318, 6, Pp. G1034-G1041.Abstract

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.

Isaac M Chiu and Asya Rolls. 6/2020. “Editorial overview: Brain, gut and immune system interactions.” Curr Opin Neurobiol, 62, Pp. iii-v. PDF
Coco Chu, David Artis, and Isaac M Chiu. 3/17/2020. “Neuro-immune Interactions in the Tissues.” Immunity, 52, 3, Pp. 464-474.Abstract
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.
Kathy Wang, Omar K Yaghi, Raul German Spallanzani, Xi Chen, David Zemmour, Nicole Lai, Isaac M Chiu, Christophe Benoist, and Diane Mathis. 3/10/2020. “Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle.” Proc Natl Acad Sci U S A, 117, 10, Pp. 5402-5408.Abstract

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.

Bing Zhang, Sai Ma, Inbal Rachmin, Megan He, Pankaj Baral, Sekyu Choi, William A Gonçalves, Yulia Shwartz, Eva M Fast, Yiqun Su, Leonard I Zon, Aviv Regev, Jason D Buenrostro, Thiago M Cunha, Isaac M Chiu, David E Fisher, and Ya-Chieh Hsu. 1/22/2020. “Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.” Nature, 577, 7792, Pp. 676-681.Abstract

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.

Nicole Y Lai, Melissa A Musser, Felipe A Pinho-Ribeiro, Pankaj Baral, Amanda Jacobson, Pingchuan Ma, David E Potts, Zuojia Chen, Donggi Paik, Salima Soualhi, Yiqing Yan, Aditya Misra, Kaitlin Goldstein, Valentina N Lagomarsino, Anja Nordstrom, Kisha N Sivanathan, Antonia Wallrapp, Vijay K Kuchroo, Roni Nowarski, Michael N Starnbach, Hailian Shi, Neeraj K Surana, Dingding An, Chuan Wu, Jun R Huh, Meenakshi Rao, and Isaac M Chiu. 1/9/2020. “Gut-Innervating Nociceptor Neurons Regulate Peyer's Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense.” Cell, 180, 1, Pp. 33-49.e22.Abstract


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.

Felipe A Pinho-Ribeiro and Isaac M Chiu. 11/2019. “Nociceptor nerves set the stage for skin immunity.” Cell Res, 29, 11, Pp. 877-878. PDF
Antonia Wallrapp, Patrick R Burkett, Samantha J Riesenfeld, Se-Jin Kim, Elena Christian, Raja-Elie E Abdulnour, Pratiksha I Thakore, Alexandra Schnell, Conner Lambden, Rebecca H Herbst, Pavana Khan, Kazutake Tsujikawa, Ramnik J Xavier, Isaac M Chiu, Bruce D Levy, Aviv Regev, and Vijay K Kuchroo. 10/15/2019. “Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses.” Immunity, 51, 4, Pp. 709-723.e6.Abstract
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.
Kimbria J Blake, Xin Ru Jiang, and Isaac M Chiu. 8/2019. “Neuronal Regulation of Immunity in the Skin and Lungs.” Trends Neurosci, 42, 8, Pp. 537-551.Abstract
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.
Pankaj Baral, Swalpa Udit, and Isaac M Chiu. 7/2019. “Pain and immunity: implications for host defence.” Nat Rev Immunol, 19, 7, Pp. 433-447.Abstract
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.
Tiphaine Voisin and Isaac M Chiu. 5/21/2019. “Mast Cells Get on Your Nerves in Itch.” Immunity, 50, 5, Pp. 1117-1119.Abstract
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.
Juan-Manuel Leyva-Castillo, Claire Galand, Christy Kam, Oliver Burton, Michael Gurish, Melissa A Musser, Jeffrey D Goldsmith, Elizabeth Hait, Samuel Nurko, Frank Brombacher, Chen Dong, Fred D Finkelman, Richard T Lee, Steven Ziegler, Isaac Chiu, Frank K Austen, and Raif S Geha. 5/21/2019. “Mechanical Skin Injury Promotes Food Anaphylaxis by Driving Intestinal Mast Cell Expansion.” Immunity, 50, 5, Pp. 1262-1275.e4.Abstract
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.
Tiphaine Voisin and Isaac M Chiu. 12/18/2018. “Molecular link between itch and atopic dermatitis.” Proc Natl Acad Sci U S A, 115, 51, Pp. 12851-12853. PDF
Felipe A Pinho-Ribeiro, Buket Baddal, Rianne Haarsma, Maghnus O'Seaghdha, Nicole J Yang, Kimbria J Blake, Makayla Portley, Waldiceu A Verri, James B Dale, Michael R Wessels, and Isaac M Chiu. 5/10/2018. “Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection.” Cell, 173, 5, Pp. 1083-1097.e22.Abstract
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.
Pankaj Baral, Benjamin D Umans, Lu Li, Antonia Wallrapp, Meghna Bist, Talia Kirschbaum, Yibing Wei, Yan Zhou, Vijay K Kuchroo, Patrick R Burkett, Bryan G Yipp, Stephen D Liberles, and Isaac M Chiu. 3/5/2018. “Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia.” Nat Med, 24, 4, Pp. 417-426.Abstract
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.
Sangeeta S Chavan, Pingchuan Ma, and Isaac M Chiu. 3/2018. “Neuro-immune interactions in inflammation and host defense: Implications for transplantation.” Am J Transplant, 18, 3, Pp. 556-563.Abstract
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.
Isaac M Chiu. 2/2018. “Infection, Pain, and Itch.” Neurosci Bull, 34, 1, Pp. 109-119.Abstract
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.
Kimbria J Blake, Pankaj Baral, Tiphaine Voisin, Ashira Lubkin, Felipe Almeida Pinho-Ribeiro, Kelsey L Adams, David P Roberson, Yuxin C Ma, Michael Otto, Clifford J Woolf, Victor J Torres, and Isaac M Chiu. 1/2/2018. “Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314.” Nat Commun, 9, 1, Pp. 37.Abstract
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.
Antonia Wallrapp, Samantha J Riesenfeld, Patrick R Burkett, Raja-Elie E Abdulnour, Jackson Nyman, Danielle Dionne, Matan Hofree, Michael S Cuoco, Christopher Rodman, Daneyal Farouq, Brian J Haas, Timothy L Tickle, John J Trombetta, Pankaj Baral, Christoph SN Klose, Tanel Mahlakõiv, David Artis, Orit Rozenblatt-Rosen, Isaac M Chiu, Bruce D Levy, Monika S Kowalczyk, Aviv Regev, and Vijay K Kuchroo. 9/21/2017. “The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation.” Nature, 549, 7672, Pp. 351-356.Abstract
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.
Nicole Y Lai, Kimbria J Blake, and Isaac M Chiu. 7/2017. “Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence.” J Intern Med, 282, 1, Pp. 5-23.Abstract
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.