MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair after Myocardial Ischemia Reperfusion Injury
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 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.
Conclusions: Our data implicate monocyte-induced MerTK-cleavage on pro-reparative MHCIILO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.
- Received May 20, 2017.
- Revision received August 23, 2017.
- Accepted August 28, 2017.