HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation
HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation
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DOI：
10.1038/s41423-023-00982-6
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发表时间：
2023-02
影响因子：
24.1
通讯作者：
Zhishuo Wang;C. Yan;Qizhen Du;Yuying Huang;Xuezhen Li;D. Zeng;Ruizhi Mao;R. Gurram;Shipeng Cheng;Wangpeng Gu;Lin Zhu;W. Fan;Liyan Ma;Z. Ling;J. Qiu;Dangsheng Li;E. Liu;Yaguang Zhang;Yiru Fang;Jinfang Zhu;Bing Sun
中科院分区：
文献类型：
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作者：
Zhishuo Wang;C. Yan;Qizhen Du;Yuying Huang;Xuezhen Li;D. Zeng;Ruizhi Mao;R. Gurram;Shipeng Cheng;Wangpeng Gu;Lin Zhu;W. Fan;Liyan Ma;Z. Ling;J. Qiu;Dangsheng Li;E. Liu;Yaguang Zhang;Yiru Fang;Jinfang Zhu;Bing Sun
第2组先天淋巴细胞（ILC 2）是一类产生细胞因子IL-5和IL-13的异质细胞，介导2型免疫反应。然而，肺ILC 2的特异性药物靶点很少报道。以前的研究表明，2型细胞因子，如IL-5和IL-13，与抑郁症有关。在这里，我们证明了抑郁症相关的单胺类神经递质5-羟色胺和ILC 2分泌的细胞因子IL-5和IL-13的抑郁症患者之间的负相关性。有趣的是，5-羟色胺通过抑制ILC 2活化来改善木瓜蛋白酶诱导的肺部炎症。我们的数据显示，5-羟色胺受体HTR 2A在小鼠肺和人PBMC的ILC 2上高度表达。此外，HTR 2A选择性激动剂（DOI）在体内和体外损害ILC 2活化并减轻2型免疫应答。在木瓜蛋白酶诱导的小鼠炎症模型中，具有ILC 2特异性HTR 2A耗竭的小鼠（Il 5cre/+·Htr 2aflox/ILC 2小鼠）消除了DOI介导的ILC 2抑制。总之，5-羟色胺和DOI可以限制2型肺部免疫应答，表明通过靶向ST 2 + ILC 2上的HTR 2A来治疗2型肺部炎症的潜在治疗策略。
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 (Il5cre/+·Htr2aflox/floxmice) 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.