Loss of NR2F6 reduces tissue-resident macrophages and protects from Salmonella typhimurium infection

Nuclear receptors regulate key functions of mononuclear phagocytes and are critical components of the innate immune system, acting as regulators of organ health and disease. In healthy mice, NR2F6 deficiency alters tissue-resident macrophage populations in the liver, lung, and spleen. In response to Salmonella Typhimurium infection, mice deficient in the nuclear receptor NR2F6 exhibit improved clinical outcomes, characterized by reduced weight loss, bacterial loads in the spleen and liver, and decreased plasma pro-inflammatory cytokines. Despite unchanged basal iron metabolism in the spleen and liver, iron regulatory proteins and the IL-6-hepcidin axis are altered in Nr2f6-deficient mice during Salmonella infection, reducing hypoferremia. Transcriptomic analysis of splenic red pulp macrophages reveals significant alterations of phagocytosis-related genes, including upregulation of Sirpa. In vitro, phagocytosis of red blood cells, regulated by the inhibitory CD47-Sirp axis, and Salmonella Typhimurium phagocytosis is significantly impaired in Nr2f6-deficient splenic macrophages. Blocking Sirp in vitro restores the phagocytic activity of Nr2f6-deficient macrophages to wild-type levels. In vivo, Salmonella Typhimurium loads are partially increased post-infection in anti-Sirp treated Nr2f6-deficient mice. These findings uncover a previously unrecognized role of NR2F6 in host-pathogen interactions, positioning it as a potential therapeutic target for infectious diseases.