期刊
AUTOPHAGY
卷 10, 期 7, 页码 1301-1315出版社
LANDES BIOSCIENCE
DOI: 10.4161/auto.28771
关键词
autophagy; experimental autoimmune encephalomyelitis; immunosuppression; mesenchymal stem cells; mitogen-activated protein kinase 1/3; prostaglandin-endoperoxide synthase 2; reactive oxygen species
类别
资金
- Ministry of Science and Technology of China [2011CB966200, 2010CB945600]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01040000]
- National Natural Science Foundation of China [81130057, 81071748, 81202113, 81190133]
- Program of Science and Technology Commission of Shanghai Municipality [11JC1411400, 11431920900, 13ZR1423200]
- Scientific Innovative Project of Shanghai Municipal Education Commission [14YZ033]
Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e. g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN 1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.
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