Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution.

Autor: Ampomah PB; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. pbampomah1@gmail.com.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA. pbampomah1@gmail.com., Cai B; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sukka SR; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Gerlach BD; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Yurdagul A Jr; Department of Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, LA, USA., Wang X; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Kuriakose G; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Darville LNF; Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Sun Y; Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA., Sidoli S; Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA., Koomen JM; Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Tall AR; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Tabas I; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. iat1@columbia.edu.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. iat1@columbia.edu.; Department of Physiology, Columbia University Irving Medical Center, New York, NY, USA. iat1@columbia.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2022 Apr; Vol. 4 (4), pp. 444-457. Date of Electronic Publication: 2022 Mar 31.
DOI: 10.1038/s42255-022-00551-7
Abstrakt: 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-β1), 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-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-PGE 2 -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/PGE 2 , 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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