The RON Receptor Tyrosine Kinase Regulates IFN-γ Production and Responses in Innate Immunity

Abstract

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 double-knockout 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.

MSP: An emerging player in metabolic syndrome

“…It was found that pretreatment of macrophages with MSP before IFN-g and LPS resulted in complete inhibition of IL-12 production through suppression of p40 expression [43]. In support of this data, RON À/À mice exhibit increased IL12p40 level in response to LPS, accompanied with elevated IFN-g level [44]. Moreover, MSP inhibited the expression of IkBz -a nuclear IkB family member which is upregulated by LPS stimulation, a positive regulator for IL-12 p40 [38].…”

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

“…MST1R encodes a cell surface receptor for macrophage-stimulating 1 (MST1, also known as MSP) with tyrosine kinase activity. Previous studies show that MST1R plays a critical function in host defense: (i) It is predominantly expressed in the tissue-resident macrophages, which promote tissue repair and inhibit inflammation by repressing the production of proinflammatory molecules induced by pathogens (14)(15)(16)(17) and (ii) MST1R expression is detected in the ciliated epithelial cells in the normal nasal mucosa, and activation of MST1R signaling can increase the ciliary motility to prevent chronic infection (18). Previous studies and our WES data strongly support the role of MST1R as an NPC susceptibility gene.…”

cAMP-dependent protein kinase activation decreases cytokine release in bronchial epithelial cells

“…Whereas swine CAFO dust-induced TNF-␣ release in monocytes is impacted by endotoxins present in the dust (31), airway epithelial cells lack lipopolysaccharide signaling proteins such as CD14 and MD-2 (3,11) and are stimulated to release TNF-␣ by the peptidoglycan contained in CAFO dust (17). In vitro, we have found that small concentrations (200 pg/ml) of swine CAFO dust-stimulated TNF-␣ are capable of inducing the autocrine/paracrine stimulation of bronchial epithelial protein kinase C-ε (PKC-ε)-dependent IL-8 release (36).…”