Macrophages Use Apoptotic Cell-Derived Methionine and DNMT3A During Efferocytosis to Promote Tissue Resolution

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.