{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T22:13:46Z","timestamp":1789424026832,"version":"build-2803163510"},"reference-count":294,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Sensory neurons at barrier tissues were once seen as passive detectors of environmental stimuli. However, in the last five years, increasing evidence has challenged this view, redefining these cells as active immune sentinels that directly affect tissue immunity in the skin, lungs, and gastrointestinal tract. Nociceptors and pruriceptors express various immune-sensing receptors, including Toll-like receptors, cytokine receptors, and alarmin sensors, which allow them to directly detect pathogens, allergens, and tissue damage. When activated, sensory neurons quickly release neuropeptides such as calcitonin gene-related peptide (CGRP), substance P, vasoactive intestinal peptide (VIP), and PACAP (pituitary adenylate cyclase-activating polypeptide), which guide immune cell recruitment, activation, and resolution. Reciprocally, immune-derived mediators, including IL-33, IL-31, thymic stromal lymphopoietin (TSLP), IL-4\/IL-13, and TNF-\u03b1, modulate neuronal excitability and plasticity, forming bidirectional neuroimmune circuits that control inflammation, host defense, pain, and itch. Landmark studies published in 2024\u20132025, including neuronal control of gut Treg function and the identification of sensory nerve immune niches, have further refined this framework and revealed tissue-specific circuit specialization. This review synthesizes recent insights from molecular, cellular, and systems levels into the sensory neuroimmune axis, emphasizes its protective versus pathogenic roles, and critically evaluates emerging therapeutic strategies and safety concerns, positioning sensory neuroimmunology as a unifying framework for tissue barrier homeostasis and disease.<\/jats:p>","DOI":"10.3390\/biology15100756","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:14:52Z","timestamp":1779452092000},"page":"756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sensory Neuroimmunology: Bidirectional Neuro-Immune Circuits Governing Pain, Itch, Inflammation, and Host Defense at Barrier Surfaces"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-1102","authenticated-orcid":false,"given":"Reza","family":"Mosaddeghi-Heris","sequence":"first","affiliation":[{"name":"Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz 5165990001, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6953-0702","authenticated-orcid":false,"given":"Nasrin","family":"Forghani","sequence":"additional","affiliation":[{"name":"Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz 5165990001, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negin","family":"Safari Dehnavi","sequence":"additional","affiliation":[{"name":"Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences (TUMS), Tehran 1136746911, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Saberivand","sequence":"additional","affiliation":[{"name":"Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 5166614756, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9718-067X","authenticated-orcid":false,"given":"Amir","family":"Tahavvori","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health System, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7573-076X","authenticated-orcid":false,"given":"Sohrab","family":"Azin","sequence":"additional","affiliation":[{"name":"Student Research Committee, Gonabad University of Medical Sciences, Gonabad 9691833181, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9514-4968","authenticated-orcid":false,"given":"Niloofar","family":"Taheri","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6556-4128","authenticated-orcid":false,"given":"Paolo","family":"Martelletti","sequence":"additional","affiliation":[{"name":"School of Health, Unitelma Sapienza University, 00185 Rome, Italy"},{"name":"Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.immuni.2024.03.008","article-title":"Sensory neurons: An integrated component of innate immunity","volume":"57","author":"Deng","year":"2024","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.mucimm.2024.10.001","article-title":"Sensory neuroimmune interactions at the barrier","volume":"17","author":"Wang","year":"2024","journal-title":"Mucosal Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.jointm.2024.01.008","article-title":"TRPV1: The key bridge in neuroimmune interactions","volume":"4","author":"Chen","year":"2024","journal-title":"J. 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