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
  • 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. [email protected].
  • 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. [email protected].
  • 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. [email protected].
  • 7. Pediatric Institute of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China. [email protected].
  • 8. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
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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