Yang Keping, Zhang Yunfeng, Xu Chenhong, Li Xin, Li Dazhu
Department of Cardiology, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jingzhou, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Immunol Cell Biol. 2016 Mar;94(3):274-84. doi: 10.1038/icb.2015.88. Epub 2015 Oct 6.
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.
心肌梗死后的炎症反应会导致心肌梗死后更严重的重塑和功能障碍。抑制心肌梗死后的炎症反应将是减轻心肌梗死后损伤和促进心脏修复的合理方法。在本研究中，我们调查了mTORC1信号通路在心肌梗死后调节性T细胞（Tregs）抗炎活性中的意义。使用野生型和Rag1(-/-)小鼠的小鼠心肌梗死模型，我们发现，雷帕霉素复合物1（mTORC1）信号通路在浸润到梗死心肌中的Tregs中上调，而不是在心肌梗死后的循环Tregs中上调。浸润性Tregs的抗炎活性明显强于循环Tregs。这通过浸润性Tregs中抗炎细胞因子的较高表达以及巨噬细胞对促炎细胞因子产生的强烈抑制得以证明。在过继转移分析中，与正常脾Tregs相比，雷帕霉素处理的脾Tregs不能有效抑制浸润性巨噬细胞的心肌梗死后炎症反应。此外，在体外培养的原代心肌细胞中，轻度氧糖剥夺处理在共培养试验中诱导了mTORC1激活和Tregs更高的抗炎活性。我们的研究确定了浸润性Tregs抑制心肌梗死后炎症的新机制。理解和利用这些信息将有助于设计针对心肌梗死的新治疗干预措施。
