Innate immune receptor driven programmed necrosis is coupled to hyper-synthesis of inflammatory lipid mediators in host defense

PROJECT SUMMARY Inflammatory responses organized by innate immune cells are critical to defend against infectious insult and initiate healing responses to injury. Mechanisms that tether the strength of the inflammatory response to the magnitude of the threat are equally important to limit unnecessarily damaging aspects of the innate immune response. Inflammatory modes of programmed cell death such as necroptosis are a critical last line of cell intrinsic defense to remove infected and irreparable cells while simultaneously creating and expanding an inflammatory state in remaining healthy tissues. How inflammatory modes of death such as necroptosis create inflammation is important to understand as it not only provides insight into the roles of necroptosis in defense against specific pathogens, but also helps to identify therapeutic targets that can be pharmaceutically leveraged to inhibit out of control inflammation in disease states typified by unregulated necroptotic death. We have identified a new regulatory circuit by which the necroptotic cell death pathway is coupled to the hyperproduction and release of inflammatory lipid mediators. The active synthesis of inflammatory lipids during necroptotic death critically requires the activity of RIP kinase 3 and may impinge upon specific phospho- lipases. We hypothesize that this linkage of cell death and lipid metabolism can significantly shape inflammatory responses in vitro and in vivo. In AIM 1 we will define the mechanism by which canonical necroptotic signals govern hyper-lipid production in primary immune cells. In AIM2 we will explore the implications of this phenomena for necroptosis associated inflammation.