mTORC1 signaling is crucial for regulatory T cells to suppress macrophage‐mediated inflammatory response after acute myocardial infarction

• Published in: Immunology and cell biology 2016-03, Vol.94 (3), p.274-284
• Main Authors: Yang, Keping, Zhang, Yunfeng, Xu, Chenhong, Li, Xin, Li, Dazhu
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - metabolism; Disease Models, Animal; Inflammation Mediators - metabolism; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - metabolism; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes - metabolism; Myocardial Infarction - complications; Myocarditis - etiology; Myocarditis - metabolism; Myocarditis - pathology; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2015.88

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.