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HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation

Cellular & Molecular Immunology volume 20, pages 404–418 (2023)Cite this article

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Abstract

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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Acknowledgements

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.

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  1. These authors contributed equally: Zhishuo Wang, Chenghua Yan, Qizhen Du, Yuying Huang, Xuezhen Li, Dan Zeng, Ruizhi Mao.

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Zhishuo Wang, Qizhen Du, Yuying Huang, Xuezhen Li, Shipeng Cheng, Wangpeng Gu, Lin Zhu, Weiguo Fan, Liyan Ma, Zhiyang Ling, Dangsheng Li, Yaguang Zhang & Bing Sun

  2. College of Life Sciences, Jiangxi University of Chinese Medicine, Nanchang, 330004, China

    Chenghua Yan

  3. Department of Respiratory Medicine Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China

    Dan Zeng & Enmei Liu

  4. Department of Allergy, Chongqing General Hospital, Chongqing, China

    Dan Zeng

  5. Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Ruizhi Mao & Yiru Fang

  6. Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Rama Krishna Gurram & Jinfang Zhu

  7. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Ju Qiu

  8. CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, 200031, China

    Yiru Fang

  9. Shanghai Key Laboratory of Psychotic Disorders, Shanghai, 201108, China

    Yiru Fang

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  1. Zhishuo Wang
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Contributions

ZW, CY, QD, YH and XL designed and performed the experiments and analyzed the data. DZ and RM collected the clinical samples. RG provided protocols and suggestions and discussed the data. SC analyzed the RNA-Seq data. WG, LZ, DL and WF contributed to discussions related to the project. LM and ZL prepared the cell lines and provided the reagents. JQ provided mice. ZW and YZ wrote the manuscript. BS, JZ, YF, EL, and YZ supervised the project and revised the manuscript.

Corresponding authors

Correspondence to Chenghua Yan, Enmei Liu, Yaguang Zhang, Yiru Fang, Jinfang Zhu or Bing Sun.

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The authors declare no competing interests.

Ethics approval

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 20, 404–418 (2023). https://doi.org/10.1038/s41423-023-00982-6

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