Background: Hepcidin is a liver-derived master regulator of iron metabolism through its molecular target ferroportin, the only known mammalian iron exporter. Accumulated evidence has shown the important roles of hepatic hepcidin in host defense and infections. Hepcidin is also expressed by airway epithelial cells. However, the function of epithelial hepcidin during bacterial pneumonia remains unknown.
Methods: Pneumonia was induced in hepcidin-1-deficient and wild-type mice using the most common bacterial agents, and the effects of hepcidin on survival, bacterial burden, iron status, and macrophage phagocytosis after bacterial pneumonia were assessed.
Results: Hepcidin levels decreased in airway epithelium during common pneumonia, while lung macrophage-derived ferroportin levels and pulmonary iron concentrations increased. Lack of hepcidin in the airway epithelium worsened the outcomes of pneumonia. Manipulation of hepcidin level in the airway epithelium in mice with macrophage-specific ferroportin deletion did not affect the progress of pneumonia. Increased pulmonary iron concentration not only facilitated bacterial growth but also led to the defective phagocytic function of lung macrophages via activation of RhoA GTPase through oxidation of RhoGDI. Furthermore, enhancing the hepcidin level in the airway epithelium rescued mice from lethal bacterial pneumonia.
Conclusions: These findings identify an uncharacterized important role of airway epithelial hepcidin in protection against bacterial pneumonia and provide the basis for novel alternative therapeutic strategies for combatting bacterial pneumonia in future translational research.