传出细胞增多
细胞生物学
MAPK/ERK通路
信号转导
细胞凋亡
癌症研究
生物
巨噬细胞
生物化学
体外
作者
Patrick B. Ampomah,Bishuang Cai,Santosh R. Sukka,Brennan D. Gerlach,Arif Yurdagul,Xiaobo Wang,George Kuriakose,Lancia Darville,Yan Sun,Simone Sidoli,John M. Koomen,Alan R. Tall,Ira Tabas
标识
DOI:10.1038/s42255-022-00551-7
摘要
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
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