Mitochondrial Phosphatase PGAM5 Negatively Regulates the Induction of Anti-inflammatory Macrophages

Abstract Macrophage polarization toward anti-inflammatory phenotypes is essential for the resolution of inflammation and restoration of tissue homeostasis, yet the mitochondrial mechanisms governing this process remain poorly defined. This study identifies a novel role for the mitochondrial membrane protein, phosphoglycerate mutase 5 (PGAM5), as a negative regulator of IL-4-driven anti-inflammatory macrophage polarization. PGAM5 selectively controls IL-4-induced phosphorylation of Janus kinase 1 (JAK1), driving the activation of the downstream transcription factor Signal transducer and activator of transcription 6 (STAT6) and thereby regulating anti-inflammatory macrophage polarization. Importantly, PGAM5-dependent regulation of anti-inflammatory responses is independent of dynamin-related protein 1 (DRP1), contrasting with the DRP1-dependent mechanism by which PGAM5 promotes pro-inflammatory macrophage responses. Furthermore, knockdown of PGAM5 markedly potentiated the IL-4-induced expression of the anti-inflammation markers, such as Il10, Tgfb, Arg1, Fizz1, and Ym1, as well as surface expression of CD163 and CD206. At the metabolic level, PGAM5 knockdown facilitated the metabolic reprogramming of macrophages toward enhanced oxidative phosphorylation and fatty acid oxidation, consistent with the bioenergetic demands of anti-inflammatory polarization. Collectively, these findings establish PGAM5 as a central regulator that oppositely controls macrophage polarization, highlighting its potential as a therapeutic target to modulate macrophage-driven inflammation and resolution.