LPS binding to TLR4 regulates hepatic stellate cell activation and fibrosis

LPS 与 TLR4 结合调节肝星状细胞活化和纤维化

• 批准号: 8606459
• 负责人: EKIHIRO SEKI
• 金额: $ 33.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606459
• 关键词: Activins; Adaptor Signaling Protein; Address; Affect; Agonist; Alcohol abuse; Alcoholic Liver Cirrhosis; Antisense Oligonucleotides; Autoimmune Diseases; Binding; Blood Circulation; Bone Marrow; Bone Morphogenetic Proteins; CCL2 gene; CCR1 gene; CCR5 gene; CX3CL1 gene; Cells; Chemotaxis; Chronic; Cirrhosis; Clinical; Complex; Deposition; Down-Regulation; Endotoxins; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Fractalkine; Genes; Genetic Transcription; Goals; Healthcare; Heavy Drinking; Hepatic; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatocyte; Infection; Inflammation; Inflammatory; Inflammatory Response; Intestines; Kupffer Cells; Link; Lipopolysaccharides; Liver Failure; Liver Fibrosis; MAP3K7 gene; MAPK8 gene; Macrophage Inflammatory Protein-1; Malignant Neoplasms; Mediating; Membrane; Molecular; Morbidity - disease rate; Mus; Mutate; Pathway interactions; Patients; Pattern recognition receptor; Phosphotransferases; Play; Population; Portal Hypertension; Prevention strategy; Prevention therapy; Primary carcinoma of the liver cells; Production; Promoter Regions; Protein Biosynthesis; RANTES; Recruitment Activity; Regulation; Repression; Resistance; Role; Signal Transduction; Staging; Symptoms; System; Testing; Transcription Factor AP-1; Viral hepatitis; base; care burden; chemokine; chemokine receptor; cytokine; design; gene induction; gut microflora; inhibitor/antagonist; liver inflammation; liver injury; liver transplantation; macrophage; migration; mortality; nonalcoholic steatohepatitis; novel therapeutic intervention; overexpression; promoter; public health relevance; receptor; response; toll-like receptor 4; transcription factor

DESCRIPTION (provided by applicant): Liver fibrosis caused by excessive alcohol consumption, viral hepatitis, autoimmune diseases, and non- alcoholic steatohepatitis (NASH), can progress to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Hepatic fibrosis is characterized by the excessive deposition of extracellular matrix, mainly produced by activated hepatic stellate cells (HSCs), and is highly associated with chronic liver inflammation. However, the precise link between inflammation and hepatic fibrosis is still unknown. Thus, understanding the molecular mechanisms of hepatic fibrosis may help to design strategies for the prevention and treatment of liver injury and fibrosis. Patients with cirrhosis show increased systemic levels of endotoxin (lipopolysaccharide, LPS). We have previously shown that Toll-like receptor 4 (TLR4), a pattern recognition receptor for LPS, plays a critical role in hepatic fibrosis. Gut microflora-derived LPS entering into the portal circulation directly activates HSCs through TLR4, but not Kupffer cells. Activation of the LPS/TLR4 pathway enhances signaling by TGF-2, the most potent fibrogenic agonist, by downregulating bone morphogenetic protein and Activin membrane bound inhibitor (Bambi), a transmembrane suppressor of TGF-2 signaling. Based on our findings, we propose to further characterize the role of TLR4 in the activation of HSCs and in hepatic fibrosis. We hypothesize that gut intestinal microflora-derived LPS binds to the TLR4 receptor in HSCs. Activated TLR4 signaling results in the formation and the release of an intracellular signaling complex. The resulting intracellular signaling activates genes including chemokines and leads to hepatic inflammation and hepatic fibrosis. The TGF-2 signaling modulator Bambi is regulated by TLR4 signaling at the promoter level in HSCs. Based on these hypotheses, we will determine the distinct roles of MyD88 and TRIF between HSCs and Kupffer cells, and TLR4-dependent receptor-associated signaling complex in HSCs (Aim 1). We will determine the regulation of Bambi at the signaling and promoter levels by LPS in HSCs (Aim 2). Moreover, we will address the role of TLR4-induced chemokines in hepatic fibrosis (Aim 3). The pursuit of these three aims will elucidate the crucial role of TLR4 signaling in HSC activation and hepatic fibrosis. The long-term goal of this project is to provide a novel therapeutic approach targeting TLR4 signaling in the prevention and therapy of liver fibrosis.

描述(申请人提供)：由过量饮酒、病毒性肝炎、自身免疫性疾病和非酒精性脂肪性肝炎(NASH)引起的肝纤维化，可进展为肝硬化、肝功能衰竭、门脉高压和肝细胞癌。肝纤维化的特点是细胞外基质过度沉积，主要由活化的肝星状细胞(HSCs)产生，与慢性肝脏炎症密切相关。然而，炎症和肝纤维化之间的确切联系仍不清楚。因此，了解肝纤维化的分子机制有助于制定防治肝损伤和肝纤维化的策略。肝硬变患者全身内毒素(内毒素，脂多糖)水平升高。我们先前已经证明，Toll样受体4(TLR4)是一种内毒素的模式识别受体，在肝纤维化中起着关键作用。肠道微生物来源的内毒素进入门静脉循环可通过TLR4直接激活HSC，但不能激活Kupffer细胞。内毒素/TLR4途径的激活通过下调骨形态发生蛋白和激活素膜结合抑制物(BAMBI)来增强最强的促纤维化激动剂转化生长因子-2(TGF-2)的信号转导。基于我们的发现，我们建议进一步研究TLR4在肝星状细胞激活和肝纤维化中的作用。我们假设肠道微生物来源的内毒素与HSCs中的TLR4受体结合。激活的TLR4信号导致细胞内信号复合体的形成和释放。由此产生的细胞内信号激活包括趋化因子在内的基因，并导致肝脏炎症和肝纤维化。在HSCs中，TLR4信号在启动子水平上调控着转化生长因子-2信号调节因子BamBI的表达。基于这些假设，我们将确定MyD88和TRIF在HSCs和Kupffer细胞之间的不同作用，以及TLR4依赖的受体相关信号复合体在HSCs中的作用(目标1)。我们将确定Bambi在信号和启动子水平对内毒素在HSCs中的调节作用(目标2)。此外，我们将讨论TLR4诱导的趋化因子在肝纤维化中的作用(目标3)。这三个目标的追求将阐明TLR4信号在HSC激活和肝纤维化中的关键作用。该项目的长期目标是提供一种针对TLR4信号通路的新的治疗方法，用于预防和治疗肝纤维化。