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（由申请人提供）：肝纤维化是由过量饮酒，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，可以发展为肝硬化，肝衰竭，门静脉高血压和肝细胞癌癌。肝纤维化的特征是细胞外基质的过度沉积，主要由活化的肝星状细胞（HSC）产生，并且与慢性肝炎高度相关。但是，炎症与肝纤维化之间的精确联系仍然未知。因此，了解肝纤维化的分子机制可能有助于设计预防和治疗肝损伤和纤维化的策略。肝硬化患者显示，内毒素的全身水平升高（脂多糖，LPS）。我们先前已经表明，Toll样受体4（TLR4）是LPS的模式识别受体，在肝纤维化中起着至关重要的作用。进入门户循环的肠道微生物衍生的LP直接通过TLR4激活HSC，而不是Kupffer细胞。 LPS/TLR4途径的激活通过下调TGF-2（最有效的纤维化激动剂TGF-2），通过下调TGF-2信号传播的跨膜抑制剂TGF-2（最有效的纤维化激动剂）。根据我们的发现，我们建议进一步表征TLR4在HSC激活和肝纤维化中的作用。我们假设肠道肠道微生物衍生的LPS与HSC中的TLR4受体结合。活化的TLR4信号传导导致细胞内信号传导复合物的形成和释放。产生的细胞内信号传导激活了包括趋化因子在内的基因，并导致肝炎症和肝纤维化。 TGF-2信号调节器BAMBI受HSC中启动子水平的TLR4信号传导调节。基于这些假设，我们将确定HSC和Kupffer细胞之间MyD88和TRIF的不同作用，以及HSC中TLR4依赖性受体相关的信号传导复合物（AIM 1）。我们将确定HSC中LPS在信号传导和启动子水平上对BAMBI的调节（AIM 2）。此外，我们将解决TLR4诱导的趋化因子在肝纤维化中的作用（AIM 3）。对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在预防和治疗肝纤维化方面提供针对TLR4信号传导的新型治疗方法。