Splenic macrophages imprinted with an antioxidative program for tissue residency and homeostasis 9109

Abstract Description M-CSF is crucial for the homeostasis of most tissue-resident macrophages, yet the underlying mechanisms may vary with specific macrophage subsets. In this regard, we found that while depriving M-CSF led to a universal reduction in tissue macrophages, only splenic macrophages were restored by simultaneous injection of antioxidant vitamin E Trolox. Mechanistically, M-CSF acts through its downstream effectors, especially mTOR, to coordinate the expression of an antioxidative program featured with ATF4/Slc7a11 and Gpx1/4 in the splenic macrophages. Genetic ablation or pharmacological blockade of mTOR led to diminished peritoneal, splenic and bone marrow macrophages. Strikingly, in vivo administering Trolox restored the splenic rather than peritoneal macrophages, supporting a tissue-specific role for the mTOR-regulated antioxidative program. Upon being challenged with chemical-induced hemolysis, the splenic macrophages also relied on mTOR/Gpx4 to constrain the oxidative stress following engulfing massive erythrocytes. Together, these results reveal a unique program required for splenic macrophage maintenance in homeostatic and pathologic settings. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)