Ischemia-reperfusion injury (IRI) related to organ procurement and cold preservation represents one of the most challenging yet understudied problems in clinical liver transplantation. Organ IRI often leads to primary graft non-function, may predispose to late chronic rejection, and contributes to acute shortage of organs available for transplantation. This project will explore the emerging function of T cell Immunoglobulin Mucin (TIM) family of cell surface proteins (expressed primarily by activate CD4+ T cells and macrophages) in the pathophysiology of hepatic IRI in a clinically relevant mouse model of extended cold storage (20h at 4C) followed by syngeneic orthotopic liver transplantation (OLT). Overall hypothesis states that signaling between macrophage TIM-4 (innate arm) and TIM-1 on CD4+ T cells (adaptive arm) regulates pro-inflammatory (pathogenic) and hepatocyte cytoprotective (homeostatic) responses during IR-stress in cold-stored OLTs.
Aim 1 : Define regulatory mechanisms of CD4+ T cell-specific TIM-1 signaling in IR-stressed OLTs. Objective 1.1: To investigate whether TIM-1 signaling polarizes hepatic CD4+ T cell function. Hypothesis: TIM- 1 blockade mitigates liver IRI by producing a T cell bias towards IL-22-STAT3/c-Myc signaling. We will study how TIM-1 activation regulates CD4+ T cell pathogenic functions in a new model of liver IRI in adoptively transferred RAG KO mice; and assess the requirement for IL-22 in hepatic cytoprotection both in vivo and in vitro. Objective 1.2: To study the mechanism by which TIM-1 - IL-22 axis exerts hepatoprotection leading to homeostasis. Hypothesis: TIM-1 blockade enhances IL-22-mediated hepatocyte autophagy. We will employ refined OLT models and well-controlled in vitro co-culture systems to dissect the requirement for autophagy pathway in hepatoprotection under TIM-1 - IL-22 regulation.
Aim 2 : Define regulatory mechanisms of macrophage-specific TIM-4 signaling in IR-stressed OLTs. Objective 2.1: To assess the mechanism of TIM-4-TLR4 inflammation response. Hypothesis: Defective macrophage TIM-4 signaling mitigates liver IR-inflammation by self-limiting feedback regulation of TLR4 activation via Foxo1/-catenin network. We will utilize a newly developed model of liver IRI in CD11b-DTR mice in which conditional ablation of adoptively transferred macrophage populations allows dissecting TIM-4- dependent cross-regulation between innate and metabolic pathways in IR-inflammation. Objective 2.2: To analyze the role of TIM-4 in hepatic phagocytosis. Hypothesis: Targeting TIM-4 inhibits local phagocytosis, to further suppress TLR4-activation response in IR-stressed livers. As TIM-4 functions as a phosphatidylserine (PS) receptor, we will apply a newly developed phagocytosis assays to study whether macrophage TIM-4 signaling regulates binding/engulfment of PS+ hepatic necrotic bodies, and contributes to the resolution of IR- inflammation.

Public Health Relevance

Liver transplantation 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, which should facilitate the development of much needed new therapies for transplant patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK102110-04
Application #
9437805
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Sherker, Averell H
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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
Yue, Shi; Zhu, Jianjun; Zhang, Ming et al. (2016) The myeloid heat shock transcription factor 1/?-catenin axis regulates NLR family, pyrin domain-containing 3 inflammasome activation in mouse liver ischemia/reperfusion injury. Hepatology 64:1683-1698

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