Efferocytosis, the clearance of apoptotic cells (ACs) by macrophages, is critical for tissue resolution, with defects driving many diseases. Mechanisms of efferocytosis-mediated resolution are incompletely understood. Here, we show that AC-derived methionine regulates resolution through epigenetic repression of the ERK1/2 phosphatase Dusp4. We focus on two key efferocytosis-induced pro-resolving mediators, PGE2 and TGFβ1, and show that efferocytosis induces Ptgs2/COX2, leading to PGE2 synthesis and PGE2-mediated induction of TGFβ1. ERK1/2 phosphorylation/activation by AC-activated CD36 is necessary for Ptgs2 induction, but this is insufficient owing to an ERK-DUSP4 negative-feedback pathway that lowers phospho-ERK. However, subsequent AC engulfment and phagolysosomal degradation repress Dusp4, enabling enhanced phospho-ERK and induction of the Ptgs2-PGE2-TGFβ1 pathway. Mechanistically, AC-derived methionine is converted to S-adenosylmethionine (SAM), which is used by DNA-methyltransferase-3A (DNMT3A) to methylate Dusp4. Bone-marrow DNMT3A deletion in mice blocks COX2/PGE2, TGFβ1, and resolution in sterile-peritonitis, apoptosis-induced thymus injury, and atherosclerosis. Knowledge of how macrophages use AC-cargo and epigenetics to induce resolution provides mechanistic insight and therapeutic options for diseases driven by impaired resolution.

SummaryThe phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro‐resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro‐resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re‐programming. Here, we review efferocytosis‐induced changes in macrophage metabolism that mediate the pro‐resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis‐fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.