Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction
Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction
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DOI：
10.1172/jci88759
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发表时间：
2017-03-01
影响因子：
15.9
通讯作者：
Epstein, Jonathan A.
中科院分区：
文献类型：
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作者：
Ramjee, Vimal;Li, Deqiang;Epstein, Jonathan A.
在美国，由心肌梗塞（MI）引起的缺血性心脏病是最普遍的心脏病形式。心肌梗死后心脏重塑是一个多方面的过程，包括成纤维细胞的激活和复杂的免疫反应。调节性T细胞（T-regulatory cells，TCFs）是CD 4（+）T细胞的一个亚群，已被证明可以抑制先天性和适应性免疫反应，并限制心肌损伤后的有害重塑。然而，受损心肌募集抑制性免疫细胞的机制在很大程度上仍然未知。在这里，我们已经显示了心外膜中Hippo信号传导通过募集TdR抑制梗死后炎症反应的作用。心外膜雅普和TAZ（两种核心Hippo通路效应物）缺陷的小鼠发生严重的MI后心包炎症和心肌纤维化，导致心肌病和死亡。突变小鼠在受损心肌中表现出较少的抑制性Tcl 4，并降低了编码IFN-γ的基因的表达，一种已知的Treg诱导剂此外，控制局部交付的IFN-。MI后，Treg向雅普/TAZ突变体的损伤心肌中的浸润得到挽救，并减少了纤维化。总的来说，这些结果表明，心外膜Hippo信号在MI后恢复阶段的适应性免疫调节中起着关键作用。
Ischemic heart disease resulting from myocardial infarction (MI) is the most prevalent form of heart disease in the United States. Post-MI cardiac remodeling is a multifaceted process that includes activation of fibroblasts and a complex immune response. T-regulatory cells (Tregs), a subset of CD4(+) T cells, have been shown to suppress the innate and adaptive immune response and limit deleterious remodeling following myocardial injury. However, the mechanisms by which injured myocardium recruits suppressive immune cells remain largely unknown. Here, we have shown a role for Hippo signaling in the epicardium in suppressing the post-infarct inflammatory response through recruitment of Tregs. Mice deficient in epicardial YAP and TAZ, two core Hippo pathway effectors, developed profound post-MI pericardial inflammation and myocardial fibrosis, resulting in cardiomyopathy and death. Mutant mice exhibited fewer suppressive Tregs in the injured myocardium and decreased expression of the gene encoding IFN-., a known Treg inducer. Furthermore, controlled local delivery of IFN-. following MI rescued Treg infiltration into the injured myocardium of YAP/TAZ mutants and decreased fibrosis. Collectively, these results suggest that epicardial Hippo signaling plays a key role in adaptive immune regulation during the post-MI recovery phase.