Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Nat Metab. 2024 Sep;6(9):1736-1755. doi: 10.1038/s42255-024-01115-7. Epub 2024 Sep 6.
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.
巨噬细胞吞噬作用可防止凋亡细胞（AC）的积累并触发炎症消退途径。将吞噬作用与消退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存在许多空白。我们现在报告说，吞噬作用触发了吲哚胺 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消退过程，包括诱导抗炎蛋白，如白细胞介素 10，并进一步增强吞噬作用。该过程始于色氨酸转运和代谢的上调，并涉及色氨酸代谢产物犬尿氨酸（Kyn）随后激活芳香烃受体（AhR）。通过这些机制，巨噬细胞中的 IDO1 和 AhR 有助于几种不同的吞噬作用依赖性组织修复的小鼠模型中适当的消退反应，特别是在由血浆低密度脂蛋白（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一种将吞噬作用与消退联系起来的综合代谢程序，这可能对非消退性慢性炎症性疾病，特别是动脉粥样硬化具有治疗意义。
