RON RECEPTOR SIGNALING ENHANCES SURVIVAL DURING INFECTIONS BY STIMULATING MACROPHAGE-DEPENDENT PRO-INFLAMMATORY MEDIATOR PRODUCTION:

The Ron receptor tyrosine kinase is expressed rather ubiquitously in most cell types including epithelial cells and peritoneal macrophage. Very little is known regarding the biology of the membrane bound Ron receptor tyrosine kinase in acute inflammation and during bacterial infections, either in vivo or in vitro. Objective: To elucidate the role of Ron receptor tyrosine kinase during non-sterile sepsis. Methods: Mice were subjected to a CLP using a 22-gauge needle (single punch) followed by a 95% ligation of the cecum. Results: Our data indicate that Ron receptor activity enhances survival following CLPinduced injury. In this model, Ron signaling augments bacterial clearance and protects against liver damage. Moreover, Ron signaling increases septic neutrophil spontaneous oxidative burst. These Ron-dependent activities are associated with elevations of IL-6, MCP-1, and MIP-2, through a mechanism likely associated with STAT-3 phosphorylation. Conclusion: The actions of the Ron receptor tyrosine kinase are beneficial during sepsis. The data suggest that Ron activity on the macrophage enhances generation of neutrophil activating mediators. This, in turn, limits bacterial spread and this likely results in the observed increased survival and mean survival times. Support: SHC Project 8560 (CC), NIH GM072760 (CC), SHC Project 8950 (SW), and NIH DK0735552 (SW).