{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T19:32:36Z","timestamp":1781724756995,"version":"3.54.5"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K07098"],"award-info":[{"award-number":["20K07098"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K06698"],"award-info":[{"award-number":["18K06698"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K07908"],"award-info":[{"award-number":["19K07908"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004330","name":"Smoking Research Foundation","doi-asserted-by":"publisher","award":["2015T001"],"award-info":[{"award-number":["2015T001"]}],"id":[{"id":"10.13039\/501100004330","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004330","name":"Smoking Research Foundation","doi-asserted-by":"publisher","award":["2020T003"],"award-info":[{"award-number":["2020T003"]}],"id":[{"id":"10.13039\/501100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (Fc\u03b5RIs) in enteric neurons. Fc\u03b5RI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that Fc\u03b5RIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.<\/jats:p>","DOI":"10.3390\/cells10071586","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T11:28:41Z","timestamp":1624447721000},"page":"1586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Pathophysiological Roles of Neuro-Immune Interactions between Enteric Neurons and Mucosal Mast Cells in the Gut of Food Allergy Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Tomoe","family":"Yashiro","sequence":"first","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanako","family":"Ogata","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2668-1997","authenticated-orcid":false,"given":"Syed Faisal","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"},{"name":"Department of Pharmacology, School of Medicine, Batterjee Medical College for Sciences and Technology, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaemin","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8304-7255","authenticated-orcid":false,"given":"Shusaku","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4383-6954","authenticated-orcid":false,"given":"Takeshi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.jaci.2013.12.1045","article-title":"Food allergy: Insights into etiology, prevention, and treatment provided by murine models","volume":"133","author":"Oyoshi","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yamamoto, T., Kodama, T., Lee, J., Utsunomiya, N., Hayashi, S., Sakamoto, H., Kuramoto, H., and Kadowaki, M. (2014). Anti-allergic role of cholinergic neuronal pathway via \u03b17 nicotinic ACh receptors on mucosal mast cells in a murine food allergy model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085888"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/nri2782","article-title":"Mast cell-orchestrated immunity to pathogens","volume":"10","author":"Soman","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1152\/physrev.1997.77.4.1033","article-title":"Mast cells","volume":"77","author":"Metcalfe","year":"1997","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.febslet.2009.11.007","article-title":"Pentagalloylglucose down-regulates mast cell surface FcepsilonRI expression in vitro and in vivo","volume":"584","author":"Suehiro","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2332\/allergolint.R-08-163","article-title":"Targeting human mast cells expressing g-protein-coupled receptors in allergic diseases","volume":"57","author":"Okayama","year":"2008","journal-title":"Allergol. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fimmu.2012.00134","article-title":"Mast cell adenosine receptors function: A focus on the a3 adenosine receptor and inflammation","volume":"3","author":"Rudich","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41385-018-0063-y","article-title":"Neuro-immune regulation of mucosal physiology","volume":"12","author":"Cardoso","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1172\/JCI124609","article-title":"Neuro-immune crosstalk and allergic inflammation","volume":"130","author":"Kabata","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.bbrc.2012.12.058","article-title":"Enhancement of CGRP sensory afferent innervation in the gut during the development of food allergy in an experimental murine model","volume":"430","author":"Lee","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"285","DOI":"10.2220\/biomedres.35.285","article-title":"CGRP, a neurotransmitter of enteric sensory neurons, contributes to the development of food allergy due to the augmentation of microtubule reorganization in mucosal mast cells","volume":"35","author":"Kim","year":"2014","journal-title":"Biomed. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00441-008-0684-7","article-title":"Immunohistochemical analysis of neuron types in the mouse small intestine","volume":"334","author":"Qu","year":"2008","journal-title":"Cell Tissue Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1096\/fj.02-1169fje","article-title":"Direct action of immunoglobulin G on primary sensory neurons through Fc gamma receptor I","volume":"18","author":"Andoh","year":"2004","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1097\/00001756-200409150-00007","article-title":"Expression of Fc epsilon receptor I on primary sensory neurons in mice","volume":"15","author":"Andoh","year":"2004","journal-title":"Neuroreport"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.jaci.2009.10.054","article-title":"Evidence for neuronal expression of functional Fc (epsilon and gamma) receptors","volume":"125","author":"Charles","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s11302-007-9088-5","article-title":"Purinergic receptors and synaptic transmission in enteric neurons","volume":"4","author":"Ren","year":"2008","journal-title":"Purinergic Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1038\/sj.bjp.0704985","article-title":"Modulation of the release of endogenous adenosine by cannabinoids in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum","volume":"137","author":"Begg","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/sj.bjp.0703123","article-title":"Molecular identification and pharmacological characterization of adenosine receptors in the guinea-pig colon","volume":"129","author":"Kadowaki","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.pharmthera.2005.04.013","article-title":"Adenosine 5\u2032-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation","volume":"112","author":"Bours","year":"2006","journal-title":"Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1365-2222.2006.02647.x","article-title":"Adenosine receptors: Novel targets for drug development in allergic rhinitis","volume":"37","author":"Matera","year":"2007","journal-title":"Clin. Exp. Allergy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.tips.2009.07.005","article-title":"Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease","volume":"30","author":"Polosa","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.intimp.2016.12.014","article-title":"Divergent regulatory roles of extracellular ATP in the degranulation response of mouse bone marrow-derived mast cells","volume":"43","author":"Yoshida","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.bbrc.2008.10.004","article-title":"IgE-induced degranulation of mucosal mast cells is negatively regulated via nicotinic acetylcholine receptors","volume":"377","author":"Suehiro","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.bbadis.2011.03.016","article-title":"Intestinal mast cells in gut inflammation and motility disturbances","volume":"1822","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bbadis.2011.06.004","article-title":"Mast cell-nerve axis with a focus on the human gut","volume":"1822","author":"Buhner","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1186\/s12974-020-02029-3","article-title":"Neurotransmitter and neuropeptide regulation of mast cell function: A systematic review","volume":"25","author":"Xu","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s11302-012-9309-4","article-title":"Cellular function and molecular structure of ecto-nucleotidases","volume":"8","author":"Zimmermann","year":"2012","journal-title":"Purinergic Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1146\/annurev-immunol-051116-052406","article-title":"Purine Release, Metabolism, and Signaling in the Inflammatory Response","volume":"37","author":"Linden","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"ref_29","first-page":"126","article-title":"Fine-tuning modulation of myenteric motoneurons by endogenous adenosine: On the role of secreted adenosine deaminase","volume":"30","author":"Vieira","year":"2006","journal-title":"Auton. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"739","DOI":"10.2174\/187152712803581092","article-title":"Ectonucleotidases and nucleotide\/nucleoside transporters as pharmacological targets for neurological disorders","volume":"11","author":"Bonan","year":"2012","journal-title":"CNS Neurol. Disord. Drug. Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jaci.2008.03.026","article-title":"Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells","volume":"122","author":"Hua","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.autneu.2006.10.003","article-title":"The bidirectional communication between neurons and mast cells within the gastrointestinal tract","volume":"133","author":"Adriaensen","year":"2007","journal-title":"Auton. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:22:24Z","timestamp":1760163744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cells10071586"],"URL":"https:\/\/doi.org\/10.3390\/cells10071586","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]}}}