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

<jats:title>Abstract</jats:title><jats:p>Hereditary hemochromatosis and iron imbalance are associated with susceptibility to bacterial infection; however, the underlying mechanisms are poorly understood. Here, we performed<jats:italic>in vivo</jats:italic>bacterial infection screening using several mouse models of hemochromatosis, including<jats:italic>Hfe</jats:italic>(<jats:italic>Hfe</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>),<jats:italic>hemojuvelin</jats:italic>(<jats:italic>Hjv</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>), and macrophage-specific<jats:italic>ferroportin-1</jats:italic>(<jats:italic>Fpn1</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup>;<jats:italic>LysM-Cre</jats:italic><jats:sup>+</jats:sup>) knockout mice. We found that<jats:italic>Hjv</jats:italic><jats:sup>−/−</jats:sup>mice, but not<jats:italic>Hfe</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>or<jats:italic>Fpn1</jats:italic><jats:sup><jats:italic>fl/fl</jats:italic></jats:sup>;<jats:italic>LysM-Cre</jats:italic><jats:sup>+</jats:sup>mice, are highly susceptible to peritoneal infection by both Gram-negative and Gram-positive bacteria. Interestingly, phagocytic cells in the peritoneum of<jats:italic>Hjv</jats:italic><jats:sup>−/−</jats:sup>mice have reduced bacterial clearance, IFN-γ secretion, and nitric oxide production; in contrast, both cell migration and phagocytosis are normal. Expressing<jats:italic>Hjv</jats:italic>in RAW264.7 cells increased the level of phosphorylated Stat1 and nitric oxide production. Moreover, macrophage-specific<jats:italic>Hjv</jats:italic>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.</jats:p>