MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury.
MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury.
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DOI：
10.1161/circresaha.117.311327
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发表时间：
2017-09-29
影响因子：
20.1
通讯作者：
Thorp EB
中科院分区：
文献类型：
--
作者：
DeBerge M;Yeap XY;Dehn S;Zhang S;Grigoryeva L;Misener S;Procissi D;Zhou X;Lee DC;Muller WA;Luo X;Rothlin C;Tabas I;Thorp EB
心肌梗死（MI）后再灌注的临床益处被先天免疫细胞功能失调所抵消，缺乏治疗干预措施。我们试图测试心肌缺血再灌注（I/R）后常驻和招募的吞噬细胞吞噬清除的意义。在人类中，我们发现心肌梗死后的临床再灌注导致可溶性MerTK（即solMER）的显著升高，MerTK是先天巨噬细胞吞噬功能受损的关键生物标志物。在再灌注小鼠中，巨噬细胞MerTK缺乏导致心脏伤口清创减少，梗死面积增加，心功能下降，这一新提示MerTK参与心肌I/R后的心脏修复。更值得注意的是，抗切割的Mertk（CR）小鼠表现出梗死面积明显减少和收缩功能改善。与其他心脏吞噬细胞亚群相比，居住的MHCIILOCCR2-巨噬细胞表达更高水平的MerTK，当暴露于凋亡细胞时，分泌促修复细胞因子，包括TGF-β。Mertk缺乏损害MHCIILO吞噬细胞的积累，这在Mertk（CR）小鼠中得到了挽救。有趣的是，阻断ccr2依赖性单核细胞浸润心脏可降低I/R后的solMER水平。我们的数据表明单核细胞诱导的MHCIILO心脏巨噬细胞的mertk切割是再灌注损伤的新因素和治疗靶点。
Clinical benefits of reperfusion after myocardial infarction (MI) are offset by maladaptive innate immune cell function and therapeutic interventions are lacking. We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion (I/R). In humans, we discovered that clinical reperfusion after MI led to significant elevation of the soluble form of MerTK (i.e. solMER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage Mertk-deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial I/R. More notably, Mertk(CR) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCIILOCCR2- macrophages expressed higher levels of MerTK and when exposed to apoptotic cells, secreted pro-reparative cytokines, including TGF-β. Mertk-deficiency compromised the accumulation of MHCIILO phagocytes, and this was rescued in Mertk(CR) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced solMER levels post I/R. Our data implicate monocyte-induced MerTK-cleavage on pro-reparative MHCIILO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.