Mitochondrial Proteomics Uncovers that Myeloid S100A9 Deficiency Promotes Liver Injury and Fibrosis Regression via Mitochondrial Metabolic Reprogramming of Macrophages.

Macrophage-mediated inflammation has been implicated in the pathogenesis of liver fibrosis. Metabolic reprogramming involves the transition of macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. S100A9 is highly expressed in activated macrophages and promotes M1 polarization; however, it is unknown whether S100A9 alters the polarization state of macrophages by regulating metabolism. This study revealed enhanced oxidative phosphorylation (OXPHOS) in S100a9-deficient bone marrow-derived macrophages (BMDMs) based on mitochondrial proteomics, characterized by increased mitochondrial fusion and elevated ATP production. Further phenotypic analysis showed that S100a9-deficient peritoneal macrophages and BMDMs exhibited an M2-like phenotype at the basal state and enhanced M2 polarization with IL-4/IL-13 stimulation, reflected by higher CD206 expression. Using the OXPHOS inhibitor oligomycin, we demonstrated that suppressing OXPHOS completely rescued the M2 polarization bias of the S100a9-deficient macrophages. Finally, we found that genetic deletion of S100A9 in myeloid cells protected against liver injury and fibrogenesis through increasing the proportion of hepatic CD206-positive M2-like anti-inflammatory macrophages in a mouse model. Our study uncovers a novel role of S100A9 in macrophage mitochondrial metabolism and phenotype reprogramming during liver fibrosis, and targeting macrophage S100A9 may be considered as a potential therapeutic strategy against liver fibrosis.