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.

胞吞作用（巨噬细胞清除凋亡细胞 (AC)）对于组织溶解至关重要，其缺陷会导致许多疾病。胞吞作用介导的溶解机制尚不完全清楚。在这里，我们发现 AC 衍生的蛋氨酸通过细胞外信号调节激酶 1/2 (ERK1/2) 磷酸酶 Dusp4 的表观遗传抑制来调节分辨率。我们重点关注两种关键的胞吞作用诱导的促溶解介质：前列腺素 E ₂ (PGE ₂ ) 和转化生长因子 β 1 (TGF-β1)，并表明胞吞作用诱导前列腺素内过氧化物合酶 2/环氧合酶 2 (Ptgs2/COX2) ，导致 PGE ₂合成和 PGE ₂介导的 TGF-β1 诱导。 AC 激活的 CD36 对 ERK1/2 进行磷酸化/激活对于 Ptgs2 诱导是必要的，但由于 ERK−DUSP4 负反馈途径会降低磷酸化 ERK，因此这是不够的。然而，随后的 AC 吞噬和吞噬溶酶体降解导致 Dusp4 抑制，从而增强 p-ERK 并诱导 Ptgs2−PGE ₂ −TGF-β1 途径。从机制上讲，AC 衍生的甲硫氨酸转化为 S-腺苷甲硫氨酸，DNA 甲基转移酶-3A (DNMT3A) 使用它来甲基化 Dusp4。小鼠骨髓 DNMT3A 缺失可阻断 COX2/PGE ₂ 、TGF-β1 以及无菌性腹膜炎、细胞凋亡诱导的胸腺损伤和动脉粥样硬化的消退。了解巨噬细胞如何利用 AC 货物和表观遗传学来诱导消退，为由消退受损驱动的疾病提供了机制见解和治疗选择。