Rationale: Clinical benefits of reperfusion after myocardial infarction (MI) are offset by maladaptive innate immune cell function and therapeutic interventions are lacking.Objective: We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion (I/R).Methods and Results: 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 MHCII^LOCCR2^- 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 MHCII^LO 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.Conclusions: Our data implicate monocyte-induced MerTK-cleavage on pro-reparative MHCII^LO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.

理由：心肌梗死（MI）后再灌注的临床益处被适应不良的先天免疫细胞功能所抵消，并且缺乏治疗干预措施。目的：我们试图检验心肌缺血再灌注（I / R）后常驻和募集吞噬细胞清除吞噬细胞的意义。方法和结果：在人类中，我们发现MI后的临床再灌注导致MerTK的可溶形式（即solMER）显着升高，MerTK是先天性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缺陷导致心肌伤口清创减少，梗塞面积增加和心脏功能下降，这在心肌I / R后新发现MerTK参与了心脏修复。更值得注意的是，对分裂具有抵抗力的Mertk（CR）小鼠表现出明显减小的梗塞面积并改善了收缩功能。相对于其他心脏吞噬细胞亚群，驻留心脏MHCII ^LO CCR2 ^-巨噬细胞表达更高水平的MERTK并且当暴露于凋亡细胞，分泌的促修复细胞因子，包括TGF-β。Mertk缺乏症损害了MHCII ^LO吞噬细胞的积累，这在Mertk（CR）中得以挽救老鼠。有趣的是，阻断CCR2依赖性单核细胞向心脏的浸润可降低I / R后的solMER水平。结论：我们的数据表明单核细胞诱导的MerTK裂解对MHCII ^LO亲原性修复巨噬细胞是再灌注损伤的新贡献者和治疗靶点。