title: mTORC1 signaling is crucial for regulatory T cells to suppress macrophage-mediated inflammatory response after acute myocardial infarction.
abstract: Post-infarction inflammatory response results in worse remodeling and dysfunction following myocardial infarction (MI). Supression of post-infarction inflammation would be a logical approach of alleviating post-infarction injury and promoting cardiac repair. In this study, we investigated the significance of mTORC1 signaling in the anti-inflammatory activity of regulatory T cells (Tregs) after MI. Using the murine MI model with wild type and Rag1(-/-) mice, we found that the mechanistic target of rapamycin compex 1 (mTORC1) signaling was upregulated in Tregs infiltrating into the infarcted myocardium, rather than in circulating Tregs after MI. The anti-inflammatory activity of infiltrating Tregs was significantly stronger than that of circulating Tregs. This was demonstrated by a higher expression of anti-inflammatory cytokines in the infiltrating Tregs and a robust suppression of proinflammatory cytokine production by macrophages. In an adoptive transfer analysis, compared with normal splenic Tregs, rapamycin-treated splenic Tregs ineffectively suppressed the post-infarction inflammatory response of infiltrating macrophages. In addition, in vitro cultured primary cardiomyocytes treated with mild oxygen glucose deprivation induced mTORC1 activation and a higher anti-inflammatory activity of Tregs in a coculture assay. Our study identified a new mechanism by which infiltrating Tregs subdue post-infarction inflammation. Understanding and utilizing this information would be helpful for designing new therapeutic interventions for MI.
authors.affiliation: Department of Cardiology, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jingzhou, China.
authors.forename: Keping
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jingzhou, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jingzhou, China.
authors.forename: Chenhong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jingzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dazhu
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications*; D009205:Myocarditis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases