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

• 批准号: 7782845
• 负责人: YUAN ZHAI
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/7782845
• 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; 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 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; Staging; T-Lymphocyte; T-Lymphocyte Subsets; 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 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

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. PUBLIC HEALTH RELEVANCE: Ischemia and reperfusion injury (IRI) in the liver is a common cause of liver failure, and occurs in many surgical procedures, including tumor resection, repair of trauma, and liver transplantation. Currently, there is no effective therapeutics to prevent or treat liver IRI in patients, due to the lack of complete understanding of the disease mechanism. This study dissects the immunological mechanism of liver IRI. Results will provide rationales for novel therapies to ameliorate liver IRI in clinics.

描述（由申请人提供）：肝脏缺血/再灌注损伤（IRI）发生在多个临床环境中，并通过导致原发性肝衰竭和移植物排斥而导致患者的发病率/死亡率。然而，尽管多年来对疾病发病机理进行了广泛研究，但目前尚无有效的疗法来改善诊所的肝脏IRI。肝脏IRI取决于肝巨噬细胞介导的局部促炎免疫反应的激活。 Kupffer细胞（KCS）和先天免疫受体TLR4。尽管肝脏IRI的发病机理并不需要外源性AG，但自适应免疫成分CD4 T细胞是必不可少的，它需要CD154，但不需要IFN-G才能进行其功能。因此，出现了关于如何激活CD4 T细胞并在这种肝脏先天免疫反应中起作用的问题。我们最近表明，肝脏IRI严重取决于CXCL10/CXCR3信号通路的激活，IR通过TLR4-IRF3型I IFN途径在肝脏中触发。 CXCL10/CXCR3信号传导的破坏在肝脏IRI的发病机理中导致两种独特的表型：肝促炎性免疫反应在CXCL10 KO小鼠中被选择性地抑制。 WT小鼠中CXCL10的缺血后中和可保护肝脏免受IRI的影响，而不会减少肝促炎性免疫反应。 CXCL10/CXCR3信号传导通过将活化的T细胞募集到炎症部位中以Ag特异性免疫反应中的趋化功能而闻名。我们建议，通过触发肝CD4 T细胞对IR的反应中的KCS和CD4 T细胞之间的联系，通过触发肝脏CD4 T细胞表达CD154并激活KCS和肝细胞中的CD40，这促进了早期的促炎性免疫激活和继发性炎症诱导的肝素损伤。通过在体内使用定义明确的鼠肝脏IRI模型在体内和巨噬细胞/T细胞/肝细胞培养物/体外共培养，我们将分析两个特定目标中细胞和分子水平的肝脏IRI中CXCL10/CXCR3信号的这些独特的调节机制。 （1）。 CXCL10/CXCR3信号传导通过鉴定其肝脏中的靶细胞及其在靶细胞中的调节免疫功能来促进肝促炎免疫激活； （2）。 CXCL10/CXCR3信号传导通过鉴定其调节的肝细胞细胞保护途径/基因来促进炎症诱导的肝细胞损伤。 CXCL10/CXCR3信号传导在KC，T细胞和肝细胞中的直接影响以及通过CD4 T细胞与KCS和肝细胞相互作用的间接效应都将得到确定。结果可能为我们提供了肝脏IRI疾病机制的关键问题之一的答案，即CD4 T细胞如何被激活并在肝TLR4介导的先天免疫反应以及新的治疗靶点中起作用，以及用于在患者中临床上临床应用的临床应用。 公共卫生相关性：肝脏中的缺血和再灌注损伤（IRI）是肝衰竭的常见原因，并且在许多外科手术过程中发生，包括肿瘤切除，创伤和肝移植。目前，由于对疾病机制缺乏完全了解，目前尚无有效的治疗剂来预防或治疗患者的肝脏IRI。这项研究剖析了肝脏IRI的免疫机制。结果将为您在诊所改善肝脏IRI的新疗法提供理由。