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‐related peptide) via pulmonary C‐fibers (PCFs), which could regulate ILC2 activity upon binding the α7 nicotinic acetylcholine receptor (α7nAChR, coded by Chrna7) or neuropeptide receptors. Whether and how α7nAChR and PCFs regulate asthma and the formation of asthma tolerance via ILC2s or iILC2s are poorly understood. We used vagotomized, PCF degeneration and Chrna7 knockout mice to investigate ovalbumin (OVA)‐induced asthma and oral OVA feeding‐induced 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 Chrna7 increased resident ILC2s and trafficking iILC2s in the lung, worsened allergic inflammation and disrupted oral tolerance. Mechanistically, deletion of Chrna7 in asthma‐tolerant conditions upregulated T helper 2 cytokine‐ (Il4, Il13 and Il25) and sphingosine‐1‐phosphate (S1P)‐related genes (S1pr1 and Sphk1). Blockade of S1P reduced iILC2 recruitment into asthmatic lungs. Our work is the first to demonstrate that vagal‐α7nAChR 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.

中文翻译：

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迷走神经-α7nAChR信号通过调节炎症组2先天淋巴细胞减弱过敏性哮喘反应并促进哮喘耐受

免疫耐受障碍可能导致过敏性哮喘。第 2 组先天淋巴细胞 (ILC2s) 和炎症性 ILC2s (iILC2s) 是哮喘的关键参与者。支配气道的迷走神经通过肺 C 纤维 (PCF) 释放乙酰胆碱或神经肽（即降钙素基因相关肽），其可在结合 α7 烟碱乙酰胆碱受体（α7nAChR，由Chrna7编码）或神经肽受体后调节 ILC2 活性。α7nAChR 和 PCF 是否以及如何通过 ILC2 或 iILC2 调节哮喘和哮喘耐受性的形成尚不清楚。我们使用迷走神经切断术、PCF 变性和Chrna7敲除小鼠以研究卵清蛋白（OVA）诱导的哮喘和口服 OVA 喂养诱导的哮喘耐受性。我们的研究结果表明，迷走神经切断术通常可以抑制肺 ILC2s 和 iILC2s，从而减轻过敏性哮喘反应但破坏哮喘耐受性。通过 PCF 变性去除神经肽也减少了肺 ILC2s 和 iILC2s，减弱了哮喘反应，但不影响哮喘耐受性。相比之下，Chrna7 的缺失增加了肺中的常驻 ILC2 和运输 iILC2，使过敏性炎症恶化并破坏了口服耐受性。机械地，缺失CHRNA7在哮喘耐受条件上调T辅助细胞因子2（IL-4 ，IL-13和IL25) 和 1-磷酸鞘氨醇 (S1P) 相关基因（S1pr1和Sphk1）。S1P 的阻断减少了 iILC2 募集到哮喘肺中。我们的工作首次证明了迷走神经-α7nAChR 信号与 iILC2s 和 S1P 的结合不仅可以缓解哮喘，还可以促进哮喘耐受。这些发现可能为通过增强哮喘耐受性来减轻哮喘提供新的治疗靶点。