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• W4220923383 abstract "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 extracellular signal-regulated kinase 1/2 (ERK1/2) phosphatase Dusp4. We focus on two key efferocytosis-induced pro-resolving mediators, prostaglandin E2 (PGE2) and transforming growth factor beta 1 (TGF-β1), and show that efferocytosis induces prostaglandin-endoperoxide synthase 2/cyclooxygenase 2 (Ptgs2/COX2), leading to PGE2 synthesis and PGE2-mediated induction of TGF-β1. 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 lead to Dusp4 repression, enabling enhanced p-ERK and induction of the Ptgs2−PGE2−TGF-β1 pathway. Mechanistically, AC-derived methionine is converted to S-adenosylmethionine, which is used by DNA methyltransferase-3A (DNMT3A) to methylate Dusp4. Bone-marrow DNMT3A deletion in mice blocks COX2/PGE2, TGF-β1, 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. Ampomah et al. show that apoptotic cell-derived methionine taken up by macrophages during efferocytosis plays a role in mediating tissue resolution by providing a substrate for DNA methylation and repression of the ERK1/2 phosphatase Dusp4, causing activation of ERK1/2 and expression of pro-resolving mediators" @default.
• W4220923383 created "2022-04-03" @default.
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• W4220923383 date "2022-03-31" @default.
• W4220923383 modified "2023-10-17" @default.
• W4220923383 title "Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution" @default.
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• W4220923383 doi "https://doi.org/10.1038/s42255-022-00551-7" @default.
• W4220923383 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35361955" @default.
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