MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury

Abstract

Rationale: Clinical benefits of reperfusion after myocardial infarction 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. Methods and Results: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), 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 ischemia reperfusion. 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 LO CCR2 − (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-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 soluble MER levels post-ischemia reperfusion. Conclusions: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCII LO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell‐induced MerTK cleavage

“…MerTK cleavage promotes necrotic core formation in advanced atherosclerosis and cardiac tissue injury in myocardial infarction. 9,31 With regard to atherosclerosis, Cai et al found that MerTK signaling stimulated the synthesis of SPMs over LTs both in isolated murine and human macrophages as well F I G U R E 5 RvD1 restores CM-induced defects in efferocytosis and MerTK cleavage. A, Macrophages were treated with Veh or 10 nM RvD1 for 20 minutes prior to the addition of conditioned media (CM) from senescent cells.…”

Down-Regulation of miR-327 Alleviates Ischemia/Reperfusion-Induced Myocardial Damage by Targeting RP105

“…However, restoration of the blood flow can induce even worse microstructural destruction, termed myocardial ischemia/reperfusion injury (MIRI), which lessens the beneficial effect of reperfusion therapy [1]. Recently, a series of in vitro and in vivo studies have demonstrated that innate inflammation, apoptosis, autophagy, platelet activation, and oxidative stress contribute to MIRI [2][3][4][5][6]. However, there is no effective strategy for limiting or preventing MIRI, so a new molecular therapeutic target is necessary.…”

Specialized functions of resident macrophages in brain and heart

“…80 these experiments indicate that cTM can incorporate large amounts of cardiomyocyte-derived material in vivo, even in the unperturbed hearts. 8 In this settings, a cTM subset expressing low levels of the major histocompatibility complex II (MHCII lo ) was phagocytically more active than other subsets both in vitro and in vivo. 8,20 This result is striking given the low renewal rate of adult cardiomyocytes, 81 and the lack of cardiomyocyte precursors.…”

“…8 In this settings, a cTM subset expressing low levels of the major histocompatibility complex II (MHCII lo ) was phagocytically more active than other subsets both in vitro and in vivo. 8,20 This result is striking given the low renewal rate of adult cardiomyocytes, 81 and the lack of cardiomyocyte precursors. It will be interesting to assess if this transfer of material from the cardiomyocyte is caused by a "trimming" process similar to synaptic pruning mediated by microglia in the brain, 3 and to define the possible mediators of this type of phagocytosis in the heart.…”

“…90 Further supporting this idea, an inactive form of Mer (solMER) was identified in the infarcted myocardium, implicating a natural mechanism of Mer inactivation after MI. 8,89 In contrast, a cleavage resistant form of Mer improves MI outcome by enhancing efferocytosis. 8 Because uptake of cell debris by macrophages after MI has been shown to induce IRF3 and type I IFN production, which are detrimental for post-MI recovery, limiting phagocytosis in the infarcted myocardium may be a way to control macrophage activation and to protect heart function.…”