Arginase-2 is Essential for IL-10 Metabolic Reprogramming of Inflammatory Macrophages at the Mitochondria

Abstract

Recent evidence highlights the importance of mitochondrial bioenergetics and dynamics in regulating macrophage polarisation. We demonstrate that Arginase-2 (Arg2), one of two arginase isoforms is an interleukin-10 (IL-10) regulated gene localized at mitochondria in inflammatory macrophages and is critical for IL-10 induced restoration of oxidative respiration in these cells. We show that IL-10 radically affects mitochondrial dynamics by promoting a state of ‘fusion’, which likely facilitates the higher oxidative bioenergetics we observe. We subsequently established that Arg2 regulates activity of succinate dehydrogenase (SDH), a bi-functional enzyme that links the mitochondrial electron transport chain (ETC) and the TCA cycle. Through its regulation of SDH, Arg2 is crucial for reversing the build-up of inflammatory mediators HIF1α and IL-1β. Moreover, we establish that Arg2 is suppressed in acute and chronic models of inflammation where IL-10 expression is compromised. These findings shed light on a new IL-10 polarization model where macrophages leverage their metabolic enzymes to enhance an anti-inflammatory state.

Keywords: interleukin-10 (IL-10), Arginase-2 (Arg2), mitochondria, fusion, oxidative phosphorylation (OxPhos), succinate dehydrogenase (SDH), interleukin-1β (IL-1β), Macrophages, mammalian target of rapamycin (mTOR), extracellular signal regulated kinase 1/2 (ERK1/2).