Group 2 innate lymphoid cells (ILC2s) are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13, which mediate the type 2 immune response. However, specific drug targets on lung ILC2s have rarely been reported. Previous studies have shown that type 2 cytokines, such as IL-5 and IL-13, are related to depression. Here, we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression. Interestingly, serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation. Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs. Furthermore, an HTR2A selective agonist (DOI) impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro. Mice with ILC2-specific depletion of HTR2A (Il5^cre/+·Htr2a^flox/flox mice) abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation. In conclusion, serotonin and DOI could restrict the type 2 lung immune response, indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2⁺ ILC2s.

第 2 组先天淋巴细胞 (ILC2) 是一类异质细胞，可产生介导 2 型免疫反应的细胞因子 IL-5 和 IL-13。然而，针对肺 ILC2 的特定药物靶点却鲜有报道。此前的研究表明，2 型细胞因子，如 IL-5 和 IL-13，与抑郁症有关。在这里，我们证明了抑郁症患者中与抑郁症相关的单胺神经递质血清素与 ILC2 分泌的细胞因子 IL-5 和 IL-13 之间存在负相关。有趣的是，血清素通过抑制 ILC2 激活来改善木瓜蛋白酶诱导的肺部炎症。我们的数据表明，血清素受体 HTR2A 在小鼠肺和人类 PBMC 的 ILC2 上高度表达。此外，HTR2A 选择性激动剂 (DOI) 会损害 ILC2 激活并减轻体内和体外 2 型免疫反应。在木瓜蛋白酶诱导的炎症小鼠模型中，ILC2 特异性缺失 HTR2A 的小鼠（ Il5 ^cre/+ ·Htr2a ^flox/flox小鼠）消除了 DOI 介导的 ILC2 抑制。总之，5-羟色胺和 DOI 可以限制 2 型肺部免疫反应，表明通过靶向 ST2 ⁺ ILC2 上的 HTR2A 来治疗 2 型肺部炎症的潜在治疗策略。