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Cell Biol."],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Disorders of immune tolerance may lead to allergic asthma. Group 2 innate lymphoid cells (ILC2s) and inflammatory ILC2s (iILC2s) are key players in asthma. The vagus nerve innervating the airways releases acetylcholine or neuropeptides (i.e. calcitonin gene\u2010related peptide) via pulmonary C\u2010fibers (PCFs), which could regulate ILC2 activity upon binding the \u03b17 nicotinic acetylcholine receptor (\u03b17nAChR, coded by <jats:italic>Chrna7<\/jats:italic>) or neuropeptide receptors. Whether and how \u03b17nAChR and PCFs regulate asthma and the formation of asthma tolerance via ILC2s or iILC2s are poorly understood. We used vagotomized, PCF degeneration and <jats:italic>Chrna7<\/jats:italic> knockout mice to investigate ovalbumin (OVA)\u2010induced asthma and oral OVA feeding\u2010induced asthma tolerance. Our results revealed that vagotomy could generally suppress lung ILC2s and iILC2s, which mitigated allergic asthma responses but disrupted asthmatic tolerance. Removal of neuropeptides by PCF degeneration also reduced lung ILC2s and iILC2s, attenuating asthma responses, but did not affect asthma tolerance. In comparison, deletion of <jats:italic>Chrna7<\/jats:italic> increased resident ILC2s and trafficking iILC2s in the lung, worsened allergic inflammation and disrupted oral tolerance. Mechanistically, deletion of <jats:italic>Chrna7<\/jats:italic> in asthma\u2010tolerant conditions upregulated T helper 2 cytokine\u2010 (<jats:italic>Il4<\/jats:italic>, <jats:italic>Il13<\/jats:italic> and <jats:italic>Il25<\/jats:italic>) and sphingosine\u20101\u2010phosphate (S1P)\u2010related genes (<jats:italic>S1pr1<\/jats:italic> and <jats:italic>Sphk1<\/jats:italic>). Blockade of S1P reduced iILC2 recruitment into asthmatic lungs. Our work is the first to demonstrate that vagal\u2010\u03b17nAChR signaling engaging with iILC2s and S1P not only alleviates asthma but also facilitates asthma tolerance. These findings may provide a novel therapeutic target for attenuating asthma by enhancing asthmatic tolerance.<\/jats:p>","DOI":"10.1111\/imcb.12400","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T15:47:30Z","timestamp":1601048850000},"page":"206-222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Vagal\u2010\u03b17nAChR signaling attenuates allergic asthma responses and facilitates asthma tolerance by regulating inflammatory group 2 innate lymphoid cells"],"prefix":"10.1111","volume":"99","author":[{"given":"Xintong","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Shanghai Fifth People\u2019s Hospital Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Unit of Respiratory Infection and Immunity 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