Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells  

作　　者：Jie Zhang Jiefang Huang Yuting Gu Mingxing Xue Fengtao Qian Bei Wang Wanlin Yang Hongshuang Yu Qiwei Wang Xin Guo Xinyuan Ding Jina Wang Min Jin Yanyun Zhang 

机构地区：[1]CAS Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai,China [2]Pediatric Institute of Soochow University,Institutes for Translational Medicine,Soochow University,Suzhou,China [3]Shanghai Institute of Immunology,Shanghai Jiao Tong University School of Medicine,Shanghai,China [4]Department of Urology and Shanghai Key Laboratory of Organ Transplantation,Zhongshan Hospital,Fudan University,Shanghai,China

出　　处：《Cellular & Molecular Immunology》2021年第6期1476-1488,共13页中国免疫学杂志（英文版）

基　　金：supported by the Ministry of Science and Technology of China(2015CB943300 and 2011CB966200);the National Natural Science Foundation of China(81873447 and 81670540);The Program of Science and Technology Commission of Shanghai Municipality(19ZR1409200 and 19ZR1430900);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01040000).

摘　　要：Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells(MSCs).However,the biological function of chaperone-mediated autophagy(CMA)in MSCs remains elusive.Here,we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ(IFN-γ)and tumor necrosis factor-α(TNF-α).In addition,suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2(LAMP-2A)in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation,and as expected,LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation.This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10(CXCL10),which recruits inflammatory cells,especially T cells,to MSCs,and inducible nitric oxide synthase(iNOS),which leads to the subsequent inhibition of T cell proliferation via nitric oxide(NO).Mechanistically,CMA inhibition dramatically promoted IFN-γplus TNF-α-induced activation of NF-κB and STAT1,leading to the enhanced expression of CXCL10 and iNOS in MSCs.Furthermore,we found that IFN-γplus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs.More interestingly,CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury.Taken together,our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines nd highlighted a previously unknown function of CMA.

关 键 词：chaperone-mediated autophagy mesenchymal stromal cells immunosuppressive capacity inflammatory microenvironment 

分 类 号：R392[医药卫生—免疫学]