Enhanced Efferocytosis of Apoptotic Cardiomyocytes Through Myeloid-Epithelial-Reproductive Tyrosine Kinase Links Acute Inflammation Resolution to Cardiac Repair After Infarction

Abstract

Rationale Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. Following myocardial infarction (MI), phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes (CMs). The molecular mechanisms of efferocytosis of CMs and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective We set out to identify mechanisms of dying cardiomyocyte (CM) engulfment by phagocytes and to for the first time assess the causal significance of disrupting efferocytosis during MI. Methods and Results In contrast to other apoptotic cell receptors, macrophage MER tyrosine kinase (MER-TK) was necessary and sufficient for efferocytosis of CMs ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic CMs, independent of changes in non-CMs, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk+/+ marrow into Mertk-/- mice corrected systolic dysfunction. Interestingly, an inactivated form of MERTK, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of MERTK inactivation post MI. Conclusions These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.

Innate Immune Mechanisms in Myocardial Infarction - An Update

“…These effects were replicated in lethally irradiated wildtype mice transplanted with bone marrow isolated from MerTK -/-animals. Conversely, transplantation of wild-type bone marrow carrying an intact Mertk gene into the MerTK -/-mice reversed the phenotype, suggesting that MerTK expression in bone marrow-derived myeloid cells is required and sufficient for an effective efferocytosis process (40). Similar results have been described for another phagocytosis receptor present on professional phagocytes, the milk fat globule epidermal growth factor 8 (Mfge8).…”

Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction

“…Among the molecules selectively upregulated in infarcted areas, Mer was recently reported to be expressed in macrophages that infiltrate the infarcted area and mediate the removal of dead cells (8). Thus, we focused on the MFG-E8/integrin α v β 5 pathway of engulfment.…”

“…Leakage of cellular contents from dead cells triggers the recruitment of inflammatory cells to the infarcted area (5). These inflammatory cells, such as macrophages and dendritic cells, have long been considered responsible for engulfment (5,8). However, the cell types that mediate the engulfment of dead cardiomyocytes generated following MI and the molecular mechanisms underlying engulfment remain unknown.…”

Monocytes and macrophages in cardiac injury and repair

“…This transitioning from inflammatory to reparative macrophages resembles in vitro polarization from the so-called "M1" to "M2" macrophages. After ingesting dead cells (a process called efferocytosis) macrophages decrease production of pro-inflammatory cytokines, such as IL-1β and TNFα, and increase production of anti-inflammatory and pro-fibrotic cytokines, such as IL-10 and transforming growth factor-β (TGFβ) (34,35). This indicates that efferocytosis may cause a shift in macrophage activation toward M2-like cells (36).…”