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）发生在多种临床环境中，并通过引起原发性肝功能衰竭和移植物排斥而导致患者发病/死亡。然而，尽管多年来对该疾病发病机制进行了广泛的研究，但目前临床上尚无有效的治疗方法来改善肝脏IRI。肝脏 IRI 依赖于肝脏巨噬细胞介导的局部促炎免疫反应的激活；库普弗细胞 (KC) 和先天免疫受体 TLR4。虽然肝脏 IRI 的发病机制不需要外源性 Ag，但适应性免疫成分 CD4 T 细胞是必不可少的，其功能需要 CD154，而不是 IFN-g。因此，问题是 CD4 T 细胞如何在肝脏先天免疫反应中被激活并发挥作用。我们最近表明，肝脏 IRI 严重依赖于 CXCL10/CXCR3 信号通路的激活，该通路是 IR 通过 TLR4-IRF3-I 型 IFN 通路在肝脏中触发的。 CXCL10/CXCR3 信号传导的破坏导致肝脏 IRI 发病机制中出现两种独特的表型：CXCL10 KO 小鼠肝脏促炎性免疫反应被选择性抑制；而 WT 小鼠中 CXCL10 的缺血后中和可保护肝脏免受 IRI 影响，且不会减弱肝脏促炎免疫反应。 CXCL10/CXCR3 信号传导因其在 Ag 特异性免疫反应中通过将活化的 T 细胞募集到炎症部位而发挥趋化功能而闻名。我们认为，它还可能通过触发肝脏 CD4 T 细胞表达 CD154 并激活 KC 和肝细胞中的 CD40，在肝脏 TLR4 对抗 IR 反应中充当 KC 和 CD4 T 细胞之间的纽带，从而促进早期促炎性免疫激活和继发性炎症诱导的肝细胞损伤。通过采用明确的体内小鼠肝脏 IRI 模型和体外巨噬细胞/T 细胞/肝细胞培养物/共培养物，我们将在细胞和分子水平上从两个特定目标分析肝脏 IRI 中 CXCL10/CXCR3 信号传导的这些独特调节机制。 (1). CXCL10/CXCR3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，促进肝脏促炎免疫激活； （2）。 CXCL10/CXCR3 信号传导通过识别其在肝细胞中调节的细胞保护途径/基因来促进炎症诱导的肝细胞损伤。将确定 CXCL10/CXCR3 信号传导对 KC、T 细胞和肝细胞的直接影响，以及通过 CD4 T 细胞与 KC 和肝细胞相互作用产生的间接影响。结果可能为我们解答肝脏IRI疾病机制的关键问题之一，即CD4 T细胞如何在肝脏TLR4介导的先天免疫反应中被激活和发挥作用，以及临床应用改善患者肝脏IRI的新治疗靶点。 公共卫生相关性：肝脏缺血再灌注损伤 (IRI) 是肝衰竭的常见原因，发生在许多外科手术中，包括肿瘤切除、创伤修复和肝移植。目前，由于对疾病机制缺乏完整的了解，尚无有效的疗法来预防或治疗患者的肝脏IRI。本研究剖析了肝脏 IRI 的免疫学机制。结果将为临床改善肝脏 IRI 的新疗法提供依据。