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/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.
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This work was supported by the Ministry of Science and Technology of China (2018YFA0507402), the National Natural Science Foundation of China (32000667), the Shanghai Science and Technology Innovation Action (21ZR1470600), and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022264). This work was also supported by the National Natural Science Foundation of China (81771465 and 81930033) and the Science and Technology Project of the Department of Education of Jiangxi Province (GJJ211248). RKG and JZ are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant 1ZIA-AI-001169) and the US‒China Biomedical Collaborative Research Program (grant AI-129775). We are grateful to Guomei Lin for breeding the animals and for animal management. We also acknowledge the individuals involved in technical support at the Center for Excellence in Molecular Cell Science, CAS, including the Core Facility for Cell Biology, the Animal Core Facility, the Core Facility of Molecular Biology and the Chemical Biology Core Facility.
The authors declare no competing interests.
All animal experiments were approved by the Institutional Animal Care and Use Committee of the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (ethics approval number SIBCB-S303-1610-030-c2). The use of depressive patient samples was approved by the Shanghai Mental Health Center (ethics approval number 2018-32). The use of healthy subject samples was approved by the Shanghai Mental Health Center (ethics approval number 2018-32). All samples were deidentified before use in the study, and all participants provided written informed consent.
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Wang, Z., Yan, C., Du, Q. et al. HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation. Cell Mol Immunol (2023). https://doi.org/10.1038/s41423-023-00982-6
- Serotonin (5-HT)
- Group 2 innate lymphoid cell
- Type 2 lung inflammation