Vagal-α7nAChR signaling attenuates allergic asthma responses and facilitates asthma tolerance by regulating inflammatory group 2 innate lymphoid cells
Vagal-α7nAChR signaling attenuates allergic asthma responses and facilitates asthma tolerance by regulating inflammatory group 2 innate lymphoid cells
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迷走神经-α7nAChR 信号通过调节炎症 2 组先天淋巴细胞来减弱过敏性哮喘反应并促进哮喘耐受
DOI：
10.1111/imcb.12400
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发表时间：
2020-12-15
影响因子：
4
通讯作者：
Su, Xiao
中科院分区：
文献类型：
--
作者：
Feng, Xintong;Li, Ling;Su, Xiao
免疫耐受障碍可能导致过敏性哮喘。第二组天然淋巴样细胞(ILC2s)和炎症性ILC2s(IILC2s)在哮喘发病中起关键作用。支配呼吸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)，可在与α7烟碱型乙酰胆碱受体(α7nAChR)或神经肽受体结合后调节ILC2的活动。α7nAChR和PCF是否以及如何通过ILC2或iILC2调节哮喘和哮喘耐受的形成尚不清楚。我们使用迷走神经切断术、PCF变性和chrna7基因敲除小鼠来研究卵白蛋白(OVA)诱导的哮喘和口服OVA喂养诱导的哮喘耐受。我们的结果表明，迷走神经切断术一般可以抑制肺内ILC2和iILC2s，从而减轻过敏性哮喘反应，但破坏哮喘耐受性。PCF变性去除神经肽也会减少肺ILC2s和iILC2s，从而减轻哮喘反应，但不影响哮喘耐受性。相比之下，chrna7基因的缺失增加了驻留的ILC2s和在肺部的贩运iILC2s，加重了变态反应性炎症，扰乱了口服耐受性。从机制上讲，在哮喘耐受性条件下，chrna 7的缺失上调了辅助性T细胞因子2(IL4、IL13和IL25)和鞘氨醇-1-磷酸(S1P)相关基因(S1PR1和Sphk1)。阻断S1P可减少iILC2在哮喘肺中的募集。我们的工作首次证明，迷走神经-α7nAChR信号与iILC2和S1P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提高哮喘耐受性来缓解哮喘提供新的治疗靶点。
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 alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR, coded by Chrna7) or neuropeptide receptors. Whether and how alpha 7nAChR 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-alpha 7nAChR 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.