Abstract
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.
Highlights
Mitochondria are important regulators of macrophage polarisation
We show that IL10-mediated induction of Arg[2] protein is essential for skewing mitochondrial dynamics and bioenergetics in inflammatory macrophages towards an oxidative phenotype, by enhancing activity of complex II (CII) at the electron transport chain (ETC)
A microarray was performed to examine gene expression changes between wild type (WT) murine bone marrow-derived macrophages (BMDM) stimulated with LPS compared to those stimulated with LPS + IL-10 or to miR155−/− BMDM stimulated with LPS, miR-155−/−(LPS) (Fig. 1a and Supplementary Fig. 1a)
Summary
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. 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-10mediated metabolic regulation, working to resolve the inflammatory status of the cell. It has been shown that in vitro ‘M1-like’ inflammatory macrophages utilize aerobic glycolysis for the generation of ATP This is accompanied with a downregulation of mitochondrial oxidative phosphorylation (OxPhos) and an accumulation of certain metabolites in the tricarboxylic acid (TCA) cycle, such as citrate and succinate[2,3]. This work highlights Arg[2] as a downstream mediator of IL-10 and provides a mechanism for its function as a resolver of inflammation
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