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.
Highlights
Autophagy takes its name from the Ancient Greek “autóphagos”, meaning “self-eating”
We found that CMA plays an essential role in the immunosuppression of MSCs induced by inflammatory factors
Our data showed that in response to the inflammatory factors TNF-α and IFN-γ, CMA was inhibited in MSCs, as manifested by decreased LAMP-2A expression at the mRNA and protein levels
Summary
Autophagy degrades intracellular components, such as proteins and organelles inside lysosomes and, as a result, contributes to cellular homeostasis, quality control, and maintenance of energetic balance.[1] Three main types of autophagy have been described, macroautophagy, microautophagy, and CMA, which differ based on the mechanisms that mediate the delivery of cytosolic cargo to lysosomes for degradation.[2] CMA was the first studied autophagy form which has selectivity for its target proteins. The CMA-related lysosomal receptor LAMP-2A forms a multimeric protein complex channel for translocation of the substrates into lysosomes. LAMP-2A is the rate-limiting component during this process and is often used as a specific target to intervene in the activity of CMA.[3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
