Targeting Myeloid Cell Iron Metabolism in Salmonella-induced Colitis

Salmonellosis is a severe infection caused by Salmonella enterica serovar Typhimurium, leading to significant global morbidity and mortality. Previous studies have shown that mice lacking the iron storage protein ferritin heavy chain (FTH1) in myeloid cells exhibit worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) directs FTH1 autophagic degradation to release iron from storage during conditions of low iron. However, the role of myeloid NCOA4 in regulating bacterial infections remains unclear. Here, we found that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages (BMDM) cells. This deficiency also increases susceptibility to Salmonella-induced colitis in mice due to exacerbated oxidative stress and ferroptosis. Our results not only give us a better understanding of myeloid iron metabolism but also pave the way for novel myeloid cell-targeted therapies to combat salmonellosis.