TIM-4 Signaling in NASH Liver Transplant Ischemia/Reperfusion Injury

/ABSTRACT Liver ischemia-reperfusion injury (IRI), resulting from the retrieval of donor organs, cold storage, and warm ischemia during the surgery, remains to be one of the main causes of morbidity and mortality in clinical orthotopic liver transplantation (OLT). Liver steatosis, the hallmark of Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), is observed in approximately 50% of deceased organ donors. Hepatic steatosis exacerbated hepatic IRI continues to be one of the major risk factors leading to primary graft dysfunction (PGD) in human OLT. Previous study has shown that stressed hepatocellular phosphatidylserine (PS) presentation induced endogenous TIM-4 expression on macrophages, which is essential for macrophage activation/phagocytosis, and further hepatocellular damage in liver IRI. The preliminary study has revealed that TIM-4 signaling is critical for foamy macrophages-mediated hepatocellular deterioration in NASH liver IRI. Hypothesis: TIM-4 signaling at the foamy macrophage (innate immune) regulates innate immune response (pathogenic), phagocytotic reprogramming (phagocytosis), hepatocellular damage (oxidative) and lipid dynamics (metabolic) during IR-stress in cold-stored murine OLTs. The following two specific aims are proposed: Aim 1: Determine whether TIM-4 derived-foamy macrophage in NASH liver graft is a risk factor for developing PGD in cold-stored murine OLTs? Aim 1 will expand upon the preliminary data using genetically modified mice (TIM-4M-KO, myeloid (macrophage) specific knockout of Timd4 gene) to evaluate pre-OLT and post-OLT TIM-4 expression on hepatic steatosis mediated-foamy macrophages in relation to PGD events in a clinically-relevant mouse model of extended hepatic cold storage followed by OLT. Aim 2: Define molecular mechanisms by which TIM-4 signaling controls foamy macrophage function in NASH liver IR-stressed OLTs. Hypothesis: TIM-4 activation promotes macrophage IRGM1 in NASH liver IRI by coupling cyclic GMP-AMP synthase (cGAS) and interferon regulatory factor 3 (IRF3), which in turn potentiates NASH liver IRI by enhancing pro-inflammatory innate responses. Aim 2 will screen for TIM-4-mediated IRGM1 promotion in NASH IRI-OLTs. Then, a new model of liver IRI in CD11b-DTR mice in which adoptive transfer of distinctive foamy-macrophage populations (after conditional depletion of native CD11b+ cells) will be utilized to dissect TIM-4–IRGM1 cross-regulation in hepatic IR-inflammation. Project Number: 1R21AI187865-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Haofeng Ji | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $433,125 | Activity Code: R21 | Study Section: Surgery, Anesthesiology and Trauma Study Section[SAT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18786501A1