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

Mitochondrial metabolism plays a crucial role in determining the functional polarization of macrophages, yet how mitochondrial signaling differentially regulates the induction of pro- and anti-inflammatory macrophages remains incompletely understood. Phosphoglycerate mutase 5 (PGAM5), a mitochondrial outer membrane phosphatase, has been implicated in promoting pro-inflammatory macrophage responses through a Dynamin-related protein 1(DRP1)-dependent metabolic reprogramming. This study identifies a distinct role for PGAM5 as a negative regulator of anti-inflammatory macrophage responses. Knockdown of PGAM5 markedly enhanced IL-4-induced expression of anti-inflammatory cytokines and M2 marker genes, including Il10, Tgfb, Arg1, Fizz1, and Ym1, as well as surface markers CD163 and CD206. PGAM5 knockdown also augmented mitochondrial oxidative metabolism and increased the expression of fatty acid oxidation/oxidative phosphorylation genes. Mechanistically, PGAM5 selectively regulated IL-4-induced phosphorylation of JAK1 without affecting STAT6 activation, as JAK1 phosphorylation was enhanced in PGAM5 KD macrophages. However, DRP1 was indispensable in IL-4-mediated induction of anti-inflammatory responses and mitochondrial respiration, indicating that PGAM5 negatively regulates anti-inflammatory macrophage polarization through DRP1-independent pathway. Collectively, these findings establish PGAM5 as a central regulator that oppositely controls macrophage polarization, highlighting its potential as a therapeutic strategy to modulate macrophage-driven inflammation and resolution.