Liver dysfunction or failure caused by ischemia and reperfusion injury (IRI) is a major problem following liver transplantation. Despite recent progress in elucidating putative mechanisms of hepatic IRI, relatively little is known on the molecular signaling pathways that facilitate liver IRI cascade. We have shown that liver IRI is an innate immunity-dominated local inflammation response. Indeed, Kupffer cells, the key components of hepatic innate immune environment, represent the first line to detect the invading pathogens in the liver. These kupffer cells readily recognize invading pathogens through chemotactic sensing and directed motility mediated by RhoA/Rho kinase (ROCK) signaling. ROCK deficiency in bone marrow-derived macrophages exhibited impaired chemotaxis and prevented the development of inflammatory disease. It was found that ROCK is a key mediator to control PTEN activity in the regulation of cell migration and chemotaxis. PTEN deficiency constitutively enhanced PI3K signaling, which in turn modulated macrophage innate immune response. Recently, we have found that ?-catenin played a key role in the regulation of immune response at the innate- adaptive interface by controlling of dendritic cell (DC) programs in hepatic IRI, suggesting the emerging role of ?-catenin signaling in modulating the DC immunogenicity and tolerogenicity in the inflammatory disease. However, it remains unknown how ?-catenin may affect macrophage-mediated innate immunity during the course of hepatic IRI. The overall goal of this proposal is to understand the intracellular signaling networks regulated by ?-catenin in IR-stressed liver. We hypothesize that ?-catenin regulates innate immunity in hepatic IRI by: 1/ controlling ROCK signaling through activation of PPAR?;and 2/ inhibiting MAPK pathways to reduce ROCK/PTEN-mediated innate immune functions. To test this hypothesis, the following specific aims are proposed: 1. Analyze the roles of PPAR? and MAPK pathways on ROCK/PTEN function in the ?-catenin-mediated immune regulation in vitro. 2. Dissect the molecular mechanisms by which ?-catenin regulates ROCK/PTEN-driven inflammatory response in vivo. These studies will increase our understanding of the hepatic regulatory networks of innate immunity in IR-induced liver inflammation. Our findings will have far reaching implications for therapeutic modulation of local ischemic tissue damage in organ transplantation, resection, and hemorrhagic shock, as well as other sterile inflammatory disease states.
This project will investigate how ?-catenin can regulate innate immune response in liver injury induced by ischemia and reperfusion. We are focused specifically on inhibition of inflammatory injury through control of intracellular signal transducton pathways in liver innate cells. These studies increase our understanding of immune regulation in liver injury has important applications not only to liver transplantation, but also other organ transplantation, tissue resection, and hemorrhagic shock, in addition to other inflammatory disease.