The RON receptor tyrosine kinase regulates IFN-γ production and responses in innate immunity

Receptor tyrosine kinases are emerging as a class of key regulators of innate immune responses. We have shown previously that the RON receptor tyrosine kinases (murine Stk), expressed on tissue-resident macrophages, inhibit classical macrophage activation while promoting hallmarks of alternative activation, thus regulating the critical balance between the inflammatory and wound-healing properties of activated macrophages. We have also shown previously that RON^-/- mice are more susceptible to in vivo endotoxin challenge than wild-type mice, suggesting that the expression of this receptor confers a degree of endotoxin resistance to these animals. Here we demonstrate that, in response to in vivo LPS challenge, RON^-/- mice harbor significantly increased systemic levels of IFN-γ and IL-12p70 and increased levels of IL-12p40 transcript in their spleen. This elevation of IFN-γ can be attributed to splenic NK cells responding to the elevated levels of IL-12. Analysis of RON and IFN-γ receptor doubleknockout mice indicates that the enhanced susceptibility of RON^-/- mice to endotoxin challenge is dependent on IFN-γ-mediated signals. In vitro studies demonstrate that stimulation of primary peritoneal macrophages with macrophage-stimulating protein, the ligand for RON, inhibits IFN-γ-induced STAT1 phosphorylation and CIITA expression, resulting in reduced surface levels of MHC class II. Further studies demonstrating the induction of suppressor of cytokine signaling 1 via macrophage-stimulating protein/RON signaling provide a potential mechanistic insight into this regulatory pathway. These results indicate that the RON receptor regulates both the production of and response to IFN-γ, resulting in enhanced susceptibility to endotoxin challenge.