School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Nat Commun. 2021 Mar 5;12(1):1460. doi: 10.1038/s41467-021-21617-2.
Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2 mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.
线粒体是巨噬细胞极化的重要调节因子。在这里，我们表明精氨酸酶 2（Arg2）是一种 microRNA-155（miR-155）和白细胞介素 10（IL-10）调节蛋白，定位于炎症巨噬细胞的线粒体中，对于 IL-10 诱导的线粒体动力学和氧化呼吸调节至关重要。在机制上，Arg2 的催化活性和在线粒体中的存在对于氧化磷酸化至关重要。我们进一步表明，Arg2 通过增加复合物 II（琥珀酸脱氢酶）的活性来介导这一过程。此外，Arg2 对于 IL-10 介导的体外炎症介质琥珀酸、缺氧诱导因子 1α（HIF-1α）和 IL-1β的下调是必需的。相应地，在使用 Arg2 小鼠的 LPS 诱导的急性炎症体内模型中，HIF-1α 和 IL-1β 高度表达。这些发现揭示了 IL-10 介导的代谢调节的一个新分支，旨在解决细胞的炎症状态。
