Journal Article

Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

Afzal, Remsha, Williams, Bryan R. G., Davey, Gavin P., Annett, Stephanie, Dettmer, Katja, Gough, Daniel J., Gearing, Linden J., Gorman, Aoife L., Cervantes-Silva, Mariana P., Duffy, Conor P., De Santi, Chiara, Bantug, Glenn R., Robson, Tracy, Hess, Christoph, Lavelle, Ed C., Hertzog, Paul J., Dowling, Jennifer K., Nally, Frances K., Oefner, Peter J., Curtis, Annie M., Davis, Gavin M., McCoy, Claire E., Hamid, Fidinny I., Assmann, Nadine, Liddicoat, Alex M., Finlay, David K.

2021

Overview

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. IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/21 / 13/31 / 13/89 / 14 / 14/19 / 14/34 / 14/63 / 38 / 38/109 / 38/39 / 38/77 / 38/88 / 38/90 / 49 / 59 / 631/250/2502/2055 / 631/250/2504/342/1726 / 631/250/256/2516 / 631/443/319 / 64 / 64/60 / 82/29 / 82/58 / 96 / 96/44 / 96/63 / Animals / Arginase / Arginase - genetics / Arginase - metabolism / Bioenergetics / Catalytic activity / Down-Regulation / Female / Humanities and Social Sciences / Hypoxia / Hypoxia-inducible factor 1a / IL-1β / Inflammation / Interleukin 10 / Interleukin-10 - metabolism / Interleukin-1beta - metabolism / Lipopolysaccharides / Macrophages / Macrophages - metabolism / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout - genetics / miRNA / Mitochondria / Mitochondria - enzymology / Mitochondria - metabolism / multidisciplinary / Oxidative phosphorylation / Phosphorylation / Regulators / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Succinate dehydrogenase / Succinate Dehydrogenase - metabolism