Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.

巨噬细胞胞吞作用可防止凋亡细胞 (AC) 积聚并触发炎症消退途径。将胞吞作用与分辨率联系起来的机制通常涉及巨噬细胞代谢的变化，但我们对这些过程的理解仍然存在许多差距。我们现在报道，胞吞作用触发了吲哚胺 2,3-双加氧酶-1 (IDO1) 依赖性色氨酸 (Trp) 代谢途径，该途径促进了几个关键的解析过程，包括诱导促解析蛋白，如白细胞介素 10，并进一步增强胞吞作用。该过程始于色氨酸转运和代谢的上调，随后涉及色氨酸代谢物犬尿氨酸 (Kyn) 激活芳烃受体 (AhR)。通过这些机制，巨噬细胞 IDO1 和 AhR 在几种不同的胞吞作用依赖性组织修复小鼠模型中有助于正确的分辨率反应，特别是在血浆低密度脂蛋白 (LDL) 降低诱导的动脉粥样硬化消退期间。这些发现揭示了巨噬细胞中的一个整合代谢程序，该程序将胞吞作用与消退联系起来，对无法消退的慢性炎症性疾病（尤其是动脉粥样硬化）可能具有治疗意义。