Active secretion of IL-33 from astrocytes is dependent on TMED10 and promotes central nervous system homeostasis

Mengya Jiao; Chenchen Wang; Xuhuan Tang; Chan Dai; Na Zhang; Anqi Fan; Zhigang Qian; Shiwang Liu; Feng Zhang; Bin Li; Yong Xu; Zheng Tan; Feili Gong; Yisheng Lu; Fang Zheng

doi:10.1016/j.bbi.2024.04.028

Active secretion of IL-33 from astrocytes is dependent on TMED10 and promotes central nervous system homeostasis

Brain Behav Immun. 2024 Apr 24:119:539-553. doi: 10.1016/j.bbi.2024.04.028. Online ahead of print.

Authors

Mengya Jiao¹, Chenchen Wang², Xuhuan Tang¹, Chan Dai¹, Na Zhang¹, Anqi Fan³, Zhigang Qian¹, Shiwang Liu¹, Feng Zhang¹, Bin Li⁴, Yong Xu², Zheng Tan⁵, Feili Gong¹, Yisheng Lu⁶, Fang Zheng⁷

Affiliations

¹ Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, China.
² National Demonstration Center for Experimental Basic Medical Education, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
³ College of Life Science, Yangtze University, Jingzhou 434025, China.
⁴ Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁵ Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China.
⁶ Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.
⁷ Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. Electronic address: zhengfangtj@hust.edu.cn.

PMID: 38663774
DOI: 10.1016/j.bbi.2024.04.028

Abstract

Interleukin-33 (IL-33), secreted by astrocytes, regulates the synapse development in the spinal cord and hippocampus and suppresses autoimmune disease in the central nervous system (CNS). However, the mechanism of unconventional protein secretion of this cytokine remains unclear. In this study, we found that IFN-γ promotes the active secretion of IL-33 from astrocytes, and the active secretion of IL-33 from cytoplasm to extracellular space was dependent on interaction with transmembrane emp24 domain 10 (TMED10) via the IL-1 like cytokine domain in astrocytes. Knockout of Il-33 or its receptor St2 induced hippocampal astrocyte activation and depressive-like disorder in naive mice, as well as increased spinal cord astrocyte activation and polarization to a neurotoxic reactive subtype and aggravated passive experimental autoimmune encephalomyelitis (EAE). Our results have identified that IL-33 is actively secreted by astrocytes through the unconventional protein secretion pathway facilitated by TMED10 channels. This process helps maintain CNS homeostasis by inhibiting astrocyte activation.

Keywords: Astrocytes; Central nervous system; Experimental autoimmune encephalomyelitis; IL-33; TMED10.