Project Summary: Ischemia reperfusion injury (IRI) is the major risk factor in liver tumor resection and transplantation. Innate immune activation drives the development of tissue injury via interactions of danger associated molecular pattern (DAMP) and pattern recognition receptors. As an integral part of the disease process, inflammation resolution in liver IRI has not been well defined. Questions of whether and how IRI may lead to transplant rejection remain to be answered. Inflammation resolution is an active process, initiated by or overlapped with immune activation. Thus, anti-inflammatory strategy by itself may potentially interfere with inflammation resolution. The pro-resolution strategy is, therefore, is critical for the true restoration of tissue homeostasis. Preliminary experiments have been performed to define inflammation resolution in a murine liver partial warm ischemia model with data on the kinetic changes in histopathology, inflammatory gene expressions and macrophages (MФs). KCs are the dominant player in the liver inflammation resolution. Their depletion by clodronate-liposomes (CL) results in significant delays in the resolution of liver IRI (14 days) with increased expressions of pro-inflammatory and fibrosis genes, as compared with the depletion of CD11b+iMФ (in CD11b- DTR mice). The KC reconstitution in these CL-treated mice restored the resolution kinetics. Experiments with TAM RTK deficient mice and TIM-4 depleting Abs showed that both Mer receptor tyrosine kinase (RTK) and TIM-4 are critical for the KC function in the resolution of liver IRI. The current project will take advantage of novel mouse genetic tools to elucidate KC-specific function in liver IRI in both partial warm ischemia, as well as liver transplantation models. Experiments are designed to test the hypothesis that embryonic KCs are the most effective reparative MФs in the resolution of liver IRI in MerTK/TIM-4 dependent manner via Liver X Receptor (LXR) - and lipoxygenase (LOX) -mediated effector pathways. Enhancement of pro-resolution function of KCs protects liver Tx and inhibits alloimmune activation. Aim 1 will determine the functional mechanism of KCs in the resolution of liver IRI. Aim 2 will define MerTK-mediated pro-resolution effector pathways in KCs. Aim 3 will determine roles of KCs in liver transplantation. Results of the study will help to delineate the inflammation resolution mechanism in liver IRI and identify novel pro-resolving therapeutic targets for future clinical application.