Airway Epithelial Hepcidin Coordinates Lung Macrophages and Immunity Against Bacterial Pneumonia

Abstract

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.

Development and Validation of a Radiomics Nomogram for Differentiating Mycoplasma Pneumonia and Bacterial Pneumonia

“…Some studies have shown that bacteria activate lung epithelial cells and produce inflammatory mediators, causing damage to lung tissue structure and epithelial cells, causing epithelial cell vacuole degeneration and mitochondrial swelling [20]. Intracellular vacuoles collect cytoplasm distortion and cell damage, which further leads to pulmonary endothelial cell apoptosis and alveolar exudation, which is manifested as alveolar consolidation on HRCT [20,21]. When the lesion involves the lung interstitial, it appears as interstitial changes on HRCT, forming peripheral interstitial inflammation.…”

The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?

“…Interference with platelet aggregation Decrease of collagen activation [ autocrine and paracrine molecule, modulating local iron homeostasis [95,96]. Not only cells of the immune system like lymphocytes, monocytes and macrophages (including alveolar macrophages) but also airway epithelial cells have been demonstrated to produce HAMP during infection and inflammation and potentially contribute to lung injury [97][98][99]. HAMP is also a peptide involved in innate antimicrobial immunity and an acute phase protein [100].…”

Macrophage ferroportin serves as a therapeutic target against bacteria-induced acute lung injury by promoting barrier restoration

“… 4 Other experimental studies also showed its regulation in macrophage function, i.e., phagocytosis and cytokine production, via the degradation of FPN, contributing to its protection in acute lung injury. 5 , 7 , 8 However, our findings revealed a previously unrecognized mechanism by which the hepcidin-FPN axis can also direct macrophages to participate in tissue regeneration following injury, thereby preserving pulmonary barrier integrity.…”

“…Bacteria-induced acute lung injury mouse models were induced by intratracheal instillations of varying amounts of bacteria. 8 , 33 In detail, 50 μL of PBS containing 2.5×10 6 colony-forming units (CFU) of Escherichia coli ( E. coli , ATCC 25922) or 5 × 10 7 CFU of Klebsiella pneumoniae ( K. pneumoniae , ATCC 13883) was intratracheally administered to mice. To further explore the role of Areg in Fpn LysM/LysM mice during lung injury, mice were treated intratracheally with IgG (normal goat IgG control, R&D, AB-108-C, 25 μg/mouse) or anti-Areg antibodies (mouse amphiregulin antibody, R&D, AF989, 25 μg/mouse) 30 min after pulmonary bacterial infections.…”

“… 6 Recently, experimental studies have indicated that macrophage FPN might be involved in the protective effects against murine lung injury because of locally produced hepcidin by airway epithelial cells. 7 , 8 However, the exact role and potential mechanism of macrophage FPN during acute lung injury remains unclear.…”