Ischemia-reperfusion injury (IRI) remains the primary obstacle limiting the success of orthotopic liver transplantation (OLT) in patients with end-stage liver disease and those with tumors of hepatic origin. Our group has pioneered the concept that hepatic IRI, an exogenous Ag-independent, innate immune-dominated sterile inflammation response, requires activated CD4+ T cells to facilitate tissue damage. T cell Immunoglobulin Mucin (TIM)-3 receptor has been recognized as a central regulator of T cell activation in a number of auto- / allo-immunity pathologies and organ transplantation. We reported that disruption of TIM-3 - Gal-9 pathway exacerbated hepatocellular injury in mouse livers subjected to warm IR. Then, we found that recipient CD4+TIM-3+ cells conferred resistance against liver IRI, suggesting a discrete host T cell subset should be spared while applying T cell-targeted therapy in transplant recipients. This proposal explores the function of TIM-3 signaling pathway in the mechanism of hepatic IRI in a clinically relevant mouse model of extended cold storage followed by orthotopic liver transplantation (OLT). First, we found that stressed hepatocytes express Gal-9 and HMGB1, i.e., known TIM-3 ligands. Second, we discovered robust expression of TIM-3 on activated liver endothelial cells (LEC). These preliminary data have led us to a central hypothesis that negative regulation between hepatocellular-derived Gal-9/HMGB1 and TIM-3 expressed on host circulating CD4+ T cells/graft LEC is essential to control tissue injury, and impose cytoprotective phenotype in IR-stressed OLT. Two interlocked specific aims will test this hypothesis:
Aim 1 : Define molecular mechanisms by which hepatocyte Gal-9 - CD4+ T cell TIM-3 negative regulation confers OLT resistance against IR stress.
Aim 1. 1. Hypothesis: Gal-9 - TIM-3 signaling triggers anti-oxidant response in which amplified Nrf2 activity represses macrophage NF?B/inflammation responses.
Aim 1. 2. Hypothesis: Gal-9 - TIM-3 signaling enhances hepatocyte autophagy via Keap1/Nrf2 redox network.
Aim 2 : Define molecular mechanisms by which hepatocellular HMGB1 - endothelial TIM-3 negative regulation alleviates IRI in OLT.
Aim 2. 1. Hypothesis: HMGB1 conditioning prior to IR insult triggers activation of liver endothelial TIM-3 to repress macrophage trafficking and sequestration in OLT.
Aim 2. 2. Hypothesis: Hepatocellular HMGB1 - endothelial TIM-3 signaling promotes LEC protective phenotype. These studies will discern novel mechanisms at the innate-adaptive immune interface, which control organ damage/promote homeostasis in IR-stressed OLT; and should contribute to the development of new therapies to increase donor organ pool and improve clinical outcomes.

Public Health Relevance

Orthotopic liver transplantation (OLT) has been established as definitive therapy for patients with end-stage liver disease. The damage to the liver associated with ischemia-reperfusion (IRI) remains one of the most understudied yet critical clinical problems. This proposal will address novel concepts in the mechanism in liver IRI and cytoprotection, which should facilitate the development of new therapies for liver transplant patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Sherker, Averell H
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Kageyama, Shoichi; Nakamura, Kojiro; Fujii, Takehiro et al. (2018) Recombinant relaxin protects liver transplants from ischemia damage by hepatocyte glucocorticoid receptor: From bench-to-bedside. Hepatology 68:258-273
Kageyama, Shoichi; Hirao, Hirofumi; Nakamura, Kojiro et al. (2018) Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside. Am J Transplant :
Zhang, Min; Nakamura, Kojiro; Kageyama, Shoichi et al. (2018) Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury. JCI Insight 3:
Kageyama, Shoichi; Nakamura, Kojiro; Ke, Bibo et al. (2018) Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation. Am J Transplant 18:1755-1763
Nakamura, Kojiro; Kageyama, Shoichi; Yue, Shi et al. (2018) Heme oxygenase-1 regulates sirtuin-1-autophagy pathway in liver transplantation: From mouse to human. Am J Transplant 18:1110-1121
Lu, Ling; Yue, Shi; Jiang, Longfeng et al. (2018) Myeloid Notch1 deficiency activates the RhoA/ROCK pathway and aggravates hepatocellular damage in mouse ischemic livers. Hepatology 67:1041-1055
Nakamura, Kojiro; Kageyama, Shoichi; Ke, Bibo et al. (2017) Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human. Liver Transpl 23:1282-1293
Palumbo, Tiziana; Nakamura, Kojiro; Lassman, Charles et al. (2017) Bruton Tyrosine Kinase Inhibition Attenuates Liver Damage in a Mouse Warm Ischemia and Reperfusion Model. Transplantation 101:322-331
Zhang, C; Zhang, Y; Liu, Y et al. (2017) A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by Nuclear Factor Erythroid 2-Related Factor 2 to Protect Liver Transplant Endothelial Cells Against Ischemia-Reperfusion Injury. Am J Transplant 17:1462-1475
Nakamura, Kojiro; Zhang, Min; Kageyama, Shoichi et al. (2017) Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol 67:1232-1242

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