Hemojuvelin regulates the innate immune response to peritoneal bacterial infection in mice

Hereditary hemochromatosis and iron imbalance are associated with susceptibility to bacterial infection; however, the underlying mechanisms are poorly understood. Here, we performed in vivo bacterial infection screening using several mouse models of hemochromatosis, including Hfe (Hfe^−/−), hemojuvelin (Hjv^−/−), and macrophage-specific ferroportin-1 (Fpn1^fl/fl; LysM-Cre⁺) knockout mice. We found that Hjv^{− / −} mice, but not Hfe^−/− or Fpn1^fl/fl;LysM-Cre⁺ mice, are highly susceptible to peritoneal infection by both Gram-negative and Gram-positive bacteria. Interestingly, phagocytic cells in the peritoneum of Hjv^{− / −} mice have reduced bacterial clearance, IFN-γ secretion, and nitric oxide production; in contrast, both cell migration and phagocytosis are normal. Expressing Hjv in RAW264.7 cells increased the level of phosphorylated Stat1 and nitric oxide production. Moreover, macrophage-specific Hjv knockout mice are susceptible to bacterial infection. Finally, we found that Hjv facilitates the secretion of IFN-γ via the IL-12/Jak2/Stat4 signaling pathway. Together, these findings reveal a novel protective role of Hjv in the early stages of antimicrobial defense.