2. Academic Validation
  3. Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells

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

  • Cell Mol Immunol. 2021 Jun;18(6):1476-1488. doi: 10.1038/s41423-019-0345-7.
Jie Zhang 1,  Jiefang Huang 1,  Yuting Gu 1,  Mingxing Xue 1,  Fengtao Qian 1,  Bei Wang 1,  Wanlin Yang 2,  Hongshuang Yu 1,  Qiwei Wang 3,  Xin Guo 2,  Xinyuan Ding 2,  Jina Wang 4,  Min Jin 5,  Yanyun Zhang 6 7 8
Affiliations

Affiliations

  • 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. wang.jina@zs-hospital.sh.cn.
  • 5 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. mjin@sibs.ac.cn.
  • 6 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. yyzhang@sibs.ac.cn.
  • 7 Pediatric Institute of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China. yyzhang@sibs.ac.cn.
  • 8 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yyzhang@sibs.ac.cn.
PMID: 31900460 DOI: 10.1038/s41423-019-0345-7
Abstract

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-γ plus 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-γ plus 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 and highlighted a previously unknown function of CMA.

Keywords

chaperone-mediated autophagy; immunosuppressive capacity; inflammatory microenvironment; mesenchymal stromal cells.

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