Tetraspan MS4A6D is a coreceptor of MHC class II antigen (MHC-II) that promotes macrophages-derived inflammation

作者全名："Chen, Yue; Li, Sirui; Huang, Xiaoyong; Wang, Chenhui; Pan, Yue; Xiang, Qun; Feng, Zeqing; Fei, Lei; Wu, Yuzhang; Ruan, Zhihua; An, Yunfei; Chen, Yongwen"

作者地址："[Chen, Yue] Southwest Univ, Inst Med, Chongqing 400033, Peoples R China; [Li, Sirui; Huang, Xiaoyong; Wang, Chenhui; Pan, Yue; Xiang, Qun; Feng, Zeqing; Fei, Lei; Wu, Yuzhang; Chen, Yongwen] Third Mil Med Univ, Inst Immunol, PLA, Chongqing 400038, Peoples R China; [Wang, Chenhui] Beijing Inst Microbiol & Epidemiol, Beijing 100071, Peoples R China; [Xiang, Qun; Feng, Zeqing] Chongqing Int Inst Immunol, Chongqing 400026, Peoples R China; [Ruan, Zhihua] Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400038, Peoples R China; [Ruan, Zhihua] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China; [An, Yunfei] Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China"

通信作者："Chen, YW (通讯作者)，Third Mil Med Univ, Inst Immunol, PLA, Chongqing 400038, Peoples R China.; Ruan, ZH (通讯作者)，Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400038, Peoples R China.; Ruan, ZH (通讯作者)，Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China.; An, YF (通讯作者)，Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China."

来源：MOLECULAR IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001039485900001

JCR分区：Q2

影响因子：3.2

年份：2023

卷号：160

期号：　

开始页：121

结束页：132

文献类型：Article

关键词：Macrophages; CREB; MHC-II; SYK

摘要："Our previous research demonstrated that the tetraspan MS4A6D is an adapter of VSIG4 that controls NLRP3 inflammasome activation (Sci Adv. 2019: eaau7426); however, the expression, distribution and biofunction of MS4A6D are still poorly understood. Here, we showed that MS4A6D is restricted to mononuclear phagocytes and that its gene transcript is controlled by the transcription factor NK2 homeobox-1 (NKX2-1). Ms4a6d-deficient (Ms4a6d-/-) mice showed normal macrophage development but manifested a greater survival advantage against endotoxin (lipopolysaccharide) challenge. Mechanistically, MS4A6D homodimers crosslinked with MHC class II antigen (MHC-II) to form a surface signaling complex under acute inflammatory conditions. MHC-II occupancy triggered Tyr241 phosphorylation in MS4A6D, leading to activation of SYK-CREB signaling cascades, further resulting in augmenting the transcription of proinflammatory genes (Il1b, Il6 and Tnfa) and amplifying the secretion of mitochondrial reactive oxygen species (mtROS). Deletion of Tyr241 or interruption of Cys237-mediated MS4A6D homodimerization in macrophages alleviated inflammation. Importantly, both Ms4a6dC237G and Ms4a6dY241G mutation mice phenocopied Ms4a6d-/- animals to prevent endotoxin lethality, highlighting MS4A6D as a novel target for treating macrophage-associated disorders."

基金机构："National Natural Science Foundation of China (NSFC) [82001693, 81771691, 81701551, 81971478]"

基金资助正文："This work was supported by The National Natural Science Foundation of China (NSFC, No. 82001693, 81771691, 81701551 and 81971478) ."