Mutations in HFE cause hereditary
hemochromatosis type I hallmarked by increased
iron absorption,
iron accumulation in hepatocytes and
iron deficiency in myeloid cells. HFE encodes an MHC-I like molecule, but its function in immune responses to
infection remains incompletely understood. Here, we investigated putative roles of Hfe in myeloid cells and hepatocytes, separately, upon
infection with Salmonella Typhimurium, an intracellular bacterium with
iron-dependent virulence. We found that constitutive and macrophage-specific deletion of Hfe protected infected mice. The propagation of Salmonella in macrophages was reduced due to limited intramacrophage
iron availability for bacterial growth and increased expression of the anti-microbial
enzyme nitric oxide synthase-2. By contrast, mice with hepatocyte-specific deletion of Hfe succumbed earlier to
Salmonella infection because of unrestricted extracellular bacterial replication associated with high
iron availability in the serum and impaired expression of essential host defense molecules such as
interleukin-6,
interferon-γ and
nitric oxide synthase-2. Wild-type mice subjected to
dietary iron overload phenocopied hepatocyte-specific Hfe deficiency suggesting that increased
iron availability in the serum is deleterious in
Salmonella infection and underlies impaired host immune responses. Moreover, the macrophage-specific effect is dominant over hepatocyte-specific Hfe-depletion, as Hfe knock-out mice have increased survival despite the higher parenchymal
iron load associated with systemic loss of Hfe. We conclude that cell-specific expression of Hfe in hepatocytes and macrophages differentially affects the course of
infections with specific pathogens by determining bacterial
iron access and the efficacy of anti-microbial immune effector pathways. This may explain the high frequency and evolutionary conservation of human HFE mutations.