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: 8434152
• 负责人: YUAN ZHAI
• 金额: $ 30.53万
• 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/8434152
• 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

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衰竭和移植排斥反应而导致患者发病率/死亡率。然而，尽管多年来对该疾病的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依赖于肝巨噬细胞介导的局部促炎免疫反应的激活；KCs与先天免疫受体TLR4。尽管外源性Ags不是肝脏IRI发病所必需的，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，CD4 T细胞是如何在肝脏先天免疫反应中被激活和发挥作用的问题就出现了。我们最近发现肝脏IRI严重依赖于CXCL10/CXCR3信号通路的激活，该信号通路在肝脏中通过TLR4- irf3 - I型IFN通路被IR触发。CXCL10/CXCR3信号的破坏导致肝脏IRI发病机制中的两种不同表型：CXCL10 KO小鼠的肝脏促炎免疫反应被选择性抑制；而在WT小鼠中，缺血后CXCL10的中和可以保护肝脏免受IRI，而不减少肝脏的促炎免疫反应。众所周知，CXCL10/CXCR3信号在ag特异性免疫反应中具有趋化功能，通过将活化的T细胞招募到炎症部位。我们提出，它也可能是肝TLR4应答中KCs和CD4 T细胞之间的联系，通过触发肝CD4 T细胞在KCs和肝细胞中表达CD154并激活CD40，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。通过体内小鼠肝脏IRI模型和体外巨噬细胞/T细胞/肝细胞培养/共培养，我们将在细胞和分子水平上分析CXCL10/CXCR3信号在肝脏IRI中的不同调节机制。（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的调节免疫功能，促进肝脏促炎免疫激活；（2）. CXCL10/CXCR3信号通过识别其在肝细胞中受调节的细胞保护途径/基因，促进炎症诱导的肝细胞损伤。CXCL10/CXCR3信号在KCs、T细胞和肝细胞中的直接作用以及通过CD4 T细胞与KCs和肝细胞相互作用的间接作用将被确定。研究结果可能为我们解答肝脏IRI发病机制中的关键问题之一，即CD4 T细胞在肝脏tlr4介导的先天免疫应答中是如何被激活和发挥作用的，并为临床应用改善患者肝脏IRI提供新的治疗靶点。