The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation

Miaomiao Han; Jingyu Ma; Suidong Ouyang; Yanyan Wang; Tingting Zheng; Peishan Lu; Zihan Zheng; Weiheng Zhao; Hongjin Li; Yun Wu; Baohua Zhang; Ran Hu; Kinya Otsu; Xinguang Liu; Ying Wan; Huabin Li; Gonghua Huang

doi:10.1038/s41423-022-00873-2

The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation

Cell Mol Immunol. 2022 Jul;19(7):805-819. doi: 10.1038/s41423-022-00873-2. Epub 2022 May 12.

Authors

Miaomiao Han^#¹, Jingyu Ma^#², Suidong Ouyang³, Yanyan Wang³, Tingting Zheng^{2

3}, Peishan Lu³, Zihan Zheng⁴, Weiheng Zhao^{2

5}, Hongjin Li^{2

6}, Yun Wu³, Baohua Zhang^{2

7}, Ran Hu^{2

8}, Kinya Otsu^{9

10}, Xinguang Liu³, Ying Wan¹¹, Huabin Li¹², Gonghua Huang^{13

14}

Affiliations

¹ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China.
² Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
³ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China.
⁴ Biomedical Analysis Center, Army Medical University, 400038, Chongqing, China.
⁵ Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
⁶ Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 200437, Shanghai, China.
⁷ Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, 200072, Shanghai, China.
⁸ Basic Department of Cancer Center, Shanghai Tenth People's Hospital of Tongji University, 200072, Shanghai, China.
⁹ Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
¹⁰ School of Cardiovascular Medicine and Sciences, King's College London, London, SE59NU, UK.
¹¹ Biomedical Analysis Center, Army Medical University, 400038, Chongqing, China. wanying516@foxmail.com.
¹² ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China. allergyli@163.com.
¹³ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. gonghua.huang@gdmu.edu.cn.
¹⁴ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China. gonghua.huang@gdmu.edu.cn.

^# Contributed equally.

Abstract

Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2-c-FOS-IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.

Keywords: Allergy; Th2; dendritic cell; p38α.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cytokines / metabolism
Dendritic Cells / metabolism
Humans
Hypersensitivity* / metabolism
Inflammation / metabolism
Mice
Mitogen-Activated Protein Kinase 14 / metabolism*
Th2 Cells* / metabolism

Substances

Cytokines
Mitogen-Activated Protein Kinase 14