Arginase-2 is Essential for IL-10 Metabolic Reprogramming of Inflammatory Macrophages at the Mitochondria
Social Science Research Network(2020)
摘要
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.
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