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

Abstract

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 (Fpn1fl/fl;LysM-Cre+) knockout mice. We found that Hjv−/− mice, but not Hfe−/− or Fpn1fl/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.

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

“…In hepatoma‐derived cells, Hjv forms a multi‐protein membrane complex with the hemochromatosis protein and transferrin receptor 2 . Recently, we found that Hjv can interact with interleukin 12 receptor subunit beta 1 . In this study, our results provide the first evidence that Hjv serves as a coreceptor for TβRII in skeletal muscle, conferring an additional layer of regulation to control TGF‐β1 signalling.…”

“…45 Recently, we found that Hjv can interact with interleukin 12 receptor subunit beta 1. 46 In this study, our results provide the first evidence that Hjv serves as a coreceptor for TβRII in skeletal muscle, conferring an additional layer of regulation to control TGF-β1 signalling. Further work is needed to determine the precise mechanism by which Hjv inhibits TGF-β1 signalling in skeletal muscle.…”

Role of Myeloid Lineage Cell Autophagy in Ischemic Brain Injury

“…The LysM Cre driver is highly efficient in recombining genes in macrophages and monocytes, 40–42 and has been shown to cause gene recombination in granulocytes. 43–45 Although LysM Cre appears reliable in recombining target genes in cultured microglia, recombination by LysM Cre driver in microglia in vivo not efficient, 20–23 reported as less than 10–25%.…”

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases

“…In contrast, invasion of cells and macrophages with bacteria, such as Listeria , Mycobacteria, or Salmonella , induces alternative mechanisms. Specifically, the upregulation of FPN by different mechanisms results in macrophage iron efflux and limitation of bacterial growth [50,51,52,53,54]. In addition, M1 macrophages and other immune cells produce several factors, such as lipocalin-2, lactoferrin, and calprotectin, which limit the bacterial access to iron [55,56,57].…”