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CXCL10/CXCR3 Signaling Regulates TLR4-Mediated Liver Inflamation and Injury

CXCL10/CXCR3 信号传导调节 TLR4 介导的肝脏炎症和损伤

基本信息

批准号：
8616058
负责人：
YUAN ZHAI
金额：
$ 31.64万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-25 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616058
关键词：
Abbreviations Address Alanine Antibodies Antigens Apoptosis Bone Marrow CD4 Positive T Lymphocytes CXC chemokine IP-10 CXCL10 gene CXCR3 gene Cell Communication Cell Culture Techniques Cell Death Cell physiology Cells Cessation of life Chimera organism Clinic Clinical Coculture Techniques Cytoprotection Development Disease Endoplasmic Reticulum Excision Functional disorder Genes Graft Rejection HMGB Proteins HMGB1 Protein Hepatocyte Immune Immune response Immunologic Receptors In Vitro Inflammation Inflammatory Inflammatory Response Injury Interferon Type II Interferons Ischemia Knock-out Kupffer Cells Ligands Link Lipopolysaccharides Liver Liver Failure Liver parenchyma Mediating Memory Metabolic Modeling Molecular Morbidity - disease rate Mus NF-kappa B Nude Mice Operative Surgical Procedures Organ Transplantation Organ failure Oxidative Stress Pathogenesis Pathway interactions Patients Peripheral Blood Lymphocyte Peroxidases Phenotype Polymerase Chain Reaction Process Recruitment Activity Regulation Reperfusion Injury Reperfusion Therapy Research Reverse Transcription Role Serum Signal Pathway Signal Transduction Site Sodium Chloride Staging T-Lymphocyte T-Lymphocyte Subsets TNF gene TNFRSF5 gene TNFSF5 gene Testing Therapeutic Toll-like receptors Transferase Trauma base biological adaptation to stress cell type clinical application effective therapy endoplasmic reticulum stress fluorescence activated cell sorter device human IRF3 protein immune activation immune function in vivo in vivo Model interferon regulatory factor-3 liver injury liver ischemia liver transplantation macrophage memory CD4 T lymphocyte mortality new therapeutic target novel prevent public health relevance reconstitution repaired response toll-like receptor 4 trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): Liver ischemia/reperfusion injury (IRI) occurs in multiple clinical settings and contributes to patient morbidity/mortality by causing primary liver failure and graft rejection. However, despite extensive research of the disease pathogenesis over the years, no effective therapies are currently available to ameliorate liver IRI in the clinics. Liver IRI is dependent on the activation of local pro-inflammatory immune response mediated by liver macrophages; Kupffer cells (KCs) and the innate immune receptor TLR4. Although exogenous Ags are not required for the pathogenesis of liver IRI, adaptive immune component CD4 T cells are indispensible, which require CD154, but not IFN-g, for their function. Thus, the question arises as to how CD4 T cells are activated and function in this liver innate immune response. We have recently shown that liver IRI is critically dependent on the activation of the CXCL10/CXCR3 signaling pathway, which is triggered in liver by IR via the TLR4- IRF3-type I IFN pathway. The disruption of CXCL10/CXCR3 signaling results in two distinctive phenotypes in the pathogenesis of liver IRI: liver pro-inflammatory immune response is selectively suppressed in CXCL10 KO mice; while post-ischemic neutralization of CXCL10 in WT mice protects livers from IRI without diminishing liver proinflammatory immune response. CXCL10/CXCR3 signaling is well known for its chemotactic function in Ag-specific immune responses by recruiting activated T cells into the inflammation site. We propose that it may also serve as the link between KCs and CD4 T cells in liver TLR4 response against IR by triggering liver CD4 T cells to express CD154 and activate CD40 in KCs and hepatocytes, which facilitates the early pro-inflammatory immune activation and the secondary inflammation induced hepatocellular injury. By employing well-defined murine liver IRI model in vivo and macrophage/T cell/hepatocyte cultures/co-cultures in vitro, we will analyze these distinctive regulatory mechanisms of CXCL10/CXCR3 signaling in liver IRI at both cellular and molecular levels in two specific aims. (1). CXCL10/CXCR3 signaling facilitates liver pro-inflammatory immune activation by identifying its target cells in the liver and its regulated immune functions in target cells; (2). CXCL10/CXCR3 signaling facilitates inflammation-induced hepatocellular injury by identifying its regulated cytoprotective pathways/genes in hepatocytes. Both the direct effects of CXCL10/CXCR3 signaling in KCs, T cells and hepatocytes as well as the indirect effect via CD4 T cell interactions with KCs and hepatocytes will be determined. Results may provide us answers to one of the key questions in the disease mechanism of liver IRI, i.e., how CD4 T cells are activated and function in liver TLR4-mediated innate immune response, as well as novel therapeutic targets for clinical application to ameliorate liver IRI in patients.

描述（由申请方提供）：肝脏缺血/再灌注损伤（IRI）发生在多种临床环境中，并通过引起原发性肝衰竭和移植物排斥反应导致患者发病率/死亡率。然而，尽管多年来对疾病发病机制进行了广泛的研究，但目前临床上没有有效的治疗方法来改善肝脏IRI。肝脏IRI依赖于由肝脏巨噬细胞、枯否细胞（KCs）和先天免疫受体TLR 4介导的局部促炎免疫应答的激活。虽然外源性Ag在肝脏IRI的发病机制中不是必需的，但适应性免疫组分CD 4 T细胞是不可缺少的，其功能需要CD 154，而不是IFN-g。因此，问题在于CD 4 T细胞如何在这种肝脏先天免疫应答中被激活和发挥作用。我们最近发现，肝脏IRI严重依赖于CXCL 10/CXCR 3信号通路的激活，这是由IR通过TLR 4-IRF 3-I型IFN通路在肝脏中触发的。CXCL 10/CXCR 3信号传导的破坏导致肝脏IRI发病机制中的两种不同表型：在CXCL 10 KO小鼠中选择性抑制肝脏促炎免疫应答;而在WT小鼠中CXCL 10的缺血后中和保护肝脏免受IRI而不减少肝脏促炎免疫应答。众所周知，CXCL 10/CXCR 3信号传导通过将活化的T细胞募集到炎症部位而在Ag特异性免疫应答中具有趋化功能。我们推测，在肝脏TLR 4抗IR反应中，CD 4 T细胞可能通过激活肝脏CD 4 T细胞表达CD 154，激活KCs和肝细胞中的CD 40，从而促进早期促炎免疫激活和继发性炎症诱导的肝细胞损伤，从而起到连接KCs和CD 4 T细胞的作用。通过采用明确的小鼠肝脏IRI体内模型和巨噬细胞/T细胞/肝细胞培养物/体外共培养物，我们将在细胞和分子水平上分析CXCL 10/CXCR 3信号转导在肝脏IRI中的这些独特的调节机制。（一）. CXCL 10/CXCR 3信号通过识别其在肝脏中的靶细胞及其在靶细胞中调节的免疫功能来促进肝脏促炎免疫活化;（2）. CXCL 10/CXCR 3信号通过识别其在肝细胞中调节的细胞保护途径/基因促进炎症诱导的肝细胞损伤。将确定KC、T细胞和肝细胞中CXCL 10/CXCR 3信号传导的直接作用以及通过CD 4 T细胞与KC和肝细胞相互作用的间接作用。这些结果可能为我们解答肝脏IRI发病机制中的一个关键问题，即，CD 4 T细胞如何在肝脏TLR 4介导的先天免疫应答中被激活和发挥作用，以及临床应用以改善患者肝脏IRI的新治疗靶点。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ischaemia-reperfusion injury in liver transplantation--from bench to bedside.

DOI：
10.1038/nrgastro.2012.225
发表时间：
2013-02
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
0
作者：
通讯作者：

The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury.

DOI：
10.1097/tp.0000000000001032
发表时间：
2016-02
期刊：
Transplantation
影响因子：
6.2
作者：
Zhou H;Zhu J;Yue S;Lu L;Busuttil RW;Kupiec-Weglinski JW;Wang X;Zhai Y
通讯作者：
Zhai Y

Hyperglycemia and liver ischemia reperfusion injury: a role for the advanced glycation endproduct and its receptor pathway.

DOI：
10.1111/ajt.13360
发表时间：
2015-11
期刊：
AMERICAN JOURNAL OF TRANSPLANTATION
影响因子：
8.8
作者：
Yue, S.;Zhou, H. M.;Zhu, J. J.;Rao, J. H.;Busuttil, R. W.;Kupiec-Weglinski, J. W.;Lu, L.;Zhai, Y.
通讯作者：
Zhai, Y.

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury.