Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.

中文翻译：

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通过偏向 FPR2 信号传导增强胞吞作用可减轻肠道炎症

有效清除垂死细胞（胞吞作用）是组织稳态的进化保守过程。胞吞作用的遗传增强表现出炎症消退和组织修复的治疗潜力。然而，由于缺乏调节靶标，增强胞吞作用的药理学方法仍然很少。在这里，我们报告了在小鼠结肠炎模型中鉴定出的鸽胺（COL），它可以增强巨噬细胞介导的胞吞作用并减轻肠道炎症。COL 通过促进 LC3 相关的吞噬作用 (LAP)（一种非典型的自噬形式）来增强胞吞作用。转录组分析和药理学表征表明，COL 是一种偏向激动剂，占据甲酰肽受体 2 (FPR2) 的配体结合口袋的一部分，FPR2 是一种参与炎症调节的 G 蛋白偶联受体。Fpr2基因的基因消除或 FPR2 拮抗剂治疗可消除 COL 诱导的胞吞作用、抗结肠炎活性和 LAP。综上所述，我们的研究将 FPR2 确定为调节 LC3 相关胞吞作用以减轻肠道炎症的潜在靶标，并强调了 COL（FPR2 的天然偏向激动剂）在治疗炎症性肠病中的治疗价值。