Ron receptor deficient alveolar myeloid cells exacerbate LPS-induced acute lung injury in the murine lung.

Previous studies have shown that the Ron receptor tyrosine kinase is an important regulator of the acute lung inflammatory response induced by intranasal administration of bacterial LPS. Compared to wild-type mice, complete loss of the Ron receptor in all cell types in vivo was associated with increased lung damage as determined by histological analyses and several markers of lung injury including increases in pro-inflammatory cytokines such as TNF-α. Tumor-necrosis factor-α is a multifunctional cytokine secreted by macrophages, which plays a major role in inflammation and is a central mediator of several disease states including rheumatoid arthritis and sepsis. Based on increased TNF-α production observed in the Ron-deficient mice, we hypothesized that Ron receptor function in the inflammatory cell compartment is essential for the regulating lung injury in vivo. To test this hypothesis, we generated myeloid lineage-specific Ron-deficient mice. In this study, we report that loss of Ron signaling selectively in myeloid cells results in increased lung injury following intranasal administration of LPS as measured by increases in TNF-α production, ensuing neutrophil accumulation and increased lung histopathology. These findings corroborate the role of Ron receptor tyrosine kinase as a negative regulator of inflammation and further demonstrate the in vivo significance of Ron signaling selectively in myeloid cells as a major regulator of this response in vivo. These data authenticate Ron as a potential target in innate immunity and TNF-α-mediated pathologies.