Journal
NATURE METABOLISM
Volume 4, Issue 4, Pages 444-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-022-00551-7
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Funding
- NIH [P30CA013696, S10OD020056, S10RR027050, R00 DK115778, T32 5T32HL007343-42, K99 HL145131, R01 HL127464, R01 HL087123, R35 HL145228, 1 S10 OD030286-01]
- Transatlantic Network of Excellence grant from the Leducq Foundation [TNE-18CVD04]
- Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant)
- AFAR (Sagol Network GerOmic Award)
- Einstein Nathan Shock Center for the Biology of Aging, Deerfield (Xseed award)
- NIH P30 grant [CA01333047]
- NIGMS [5 R01GM129350-04]
- Proteomics & Metabolomics Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center [P30-CA076292]
- [R00DK115778]
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This study demonstrates that methionine derived from apoptotic cells taken up by macrophages during efferocytosis plays a role in mediating tissue resolution by providing a substrate for DNA methylation and repressing the expression of the ERK1/2 phosphatase Dusp4, leading to activation of ERK1/2 and the expression of pro-resolving mediators.
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 E-2 (PGE(2)) and transforming growth factor beta 1 (TGF-beta 1), and show that efferocytosis induces prostaglandin-endoperoxide synthase 2/cyclooxygenase 2 (Ptgs2/COX2), leading to PGE(2) synthesis and PGE(2)-mediated induction of TGF-beta 1. 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-PGE(2)-TGF-beta 1 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/PGE(2), TGF-beta 1, 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
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