Publications

2021
Liwen Deng and Isaac M Chiu. 4/1/2021. “Microbes and pain.” PLoS Pathog, 17, 4, Pp. e1009398. PDF
Tiphaine Voisin, Caroline Perner, Marie-Angele Messou, Stephanie Shiers, Saltanat Ualiyeva, Yoshihide Kanaoka, Theodore J Price, Caroline L Sokol, Lora G Bankova, Frank K Austen, and Isaac M Chiu. 3/30/2021. “The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.” Proc Natl Acad Sci U S A, 118, 13.Abstract
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.
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Yiqing Yan, Deepshika Ramanan, Milena Rozenberg, Kelly McGovern, Daniella Rastelli, Brinda Vijaykumar, Omar Yaghi, Tiphaine Voisin, Munir Mosaheb, Isaac Chiu, Shalev Itzkovitz, Meenakshi Rao, Diane Mathis, and Christophe Benoist. 3/9/2021. “Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut.” Immunity, 54, 3, Pp. 499-513.e5.Abstract
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.
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Amanda Jacobson, Daping Yang, Madeleine Vella, and Isaac M Chiu. 2/4/2021. “The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes.” Mucosal Immunol.Abstract
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.
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Liliana M Sanmarco, Michael A Wheeler, Cristina Gutiérrez-Vázquez, Carolina Manganeli Polonio, Mathias Linnerbauer, Felipe A Pinho-Ribeiro, Zhaorong Li, Federico Giovannoni, Katelyn V Batterman, Giulia Scalisi, Stephanie EJ Zandee, Evelyn S Heck, Moneera Alsuwailm, Douglas L Rosene, Burkhard Becher, Isaac M Chiu, Alexandre Prat, and Francisco J Quintana. 2/2021. “Gut-licensed IFNγ+ NK cells drive LAMP1+ TRAIL+ anti-inflammatory astrocytes.” Nature, 590, 7846, Pp. 473-479.Abstract
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.
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2020
Valentina N Lagomarsino, Aleksandar D Kostic, and Isaac M Chiu. 12/11/2020. “Mechanisms of microbial–neuronal interactions in pain and nociception.” Neurobiol Pain, 9, Pp. 100056-100056.Abstract
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.
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Caroline Perner, Cameron H Flayer, Xueping Zhu, Pamela A Aderhold, Zaynah NA Dewan, Tiphaine Voisin, Ryan B Camire, Ohn A Chow, Isaac M Chiu, and Caroline L Sokol. 11/17/2020. “Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens.” Immunity, 53, 5, Pp. 1063-1077.Abstract

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.

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Meng Wu, Yaobing Chen, Han Xia, Changli Wang, Chin Yee Tan, Xunhui Cai, Yufeng Liu, Fenghu Ji, Peng Xiong, Ran Liu, Yuanlin Guan, Yaqi Duan, Dong Kuang, Sanpeng Xu, Hanghang Cai, Qin Xia, Dehua Yang, Ming-Wei Wang, Isaac M Chiu, Chao Cheng, Philip P Ahern, Liang Liu, Guoping Wang, Neeraj K Surana, Tian Xia, and Dennis L Kasper. 11/10/2020. “Transcriptional and proteomic insights into the host response in fatal COVID-19 cases.” Proc Natl Acad Sci U S A, 117, 45, Pp. 28336-28343.Abstract

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.

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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.

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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.
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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.

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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.

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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.

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2019
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.
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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.
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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.
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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.
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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.
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