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.

Efferocytosis，巨噬细胞清除凋亡细胞 (AC)，对于组织分辨率至关重要，缺陷会导致许多疾病。efferocytosis 介导的解决机制尚不完全清楚。在这里，我们表明 AC 衍生的甲硫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。我们专注于两种关键的细胞增多症诱导的促分解介质，前列腺素 E ₂ (PGE ₂ ) 和转化生长因子 β 1 (TGF-β1)，并表明细胞增多症诱导前列腺素-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 的磷酸化/激活是 Ptgs2 诱导所必需的，但这还不够，因为 ERK-DUSP4 负反馈通路会降低磷酸化 ERK。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 和诱导 Ptgs2-PGE ₂ -TGF-β1 通路。从机制上讲，AC 衍生的甲硫氨酸被转化为 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 缺失阻断 COX2/PGE ₂、TGF-β1，以及在无菌性腹膜炎、细胞凋亡诱导的胸腺损伤和动脉粥样硬化中的消退。了解巨噬细胞如何使用 AC-cargo 和表观遗传学来诱导分辨率，为分辨率受损驱动的疾病提供了机制洞察力和治疗选择。