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

基本信息

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
项目类别：
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

项目摘要

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）：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、门静脉高压和肝细胞癌。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（HSC）产生，与慢性肝脏炎症高度相关。然而，炎症与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。肝硬化患者的内毒素（脂多糖，LPS）全身水平升高。我们之前已经证明，Toll 样受体 4 (TLR4)（一种 LPS 模式识别受体）在肝纤维化中发挥着关键作用。肠道菌群来源的 LPS 进入门脉循环后，可通过 TLR4 直接激活 HSC，但不会激活 Kupffer 细胞。 LPS/TLR4 通路的激活通过下调骨形态发生蛋白和 Activin 膜结合抑制剂 (Bambi)（一种 TGF-2 信号传导的跨膜抑制剂）来增强 TGF-2（最有效的纤维形成激动剂）的信号传导。基于我们的发现，我们建议进一步表征 TLR4 在 HSC 激活和肝纤维化中的作用。我们假设肠道微生物群衍生的 LPS 与 HSC 中的 TLR4 受体结合。激活的 TLR4 信号传导导致细胞内信号传导复合物的形成和释放。由此产生的细胞内信号传导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。 TGF-2 信号传导调节剂 Bambi 在 HSC 的启动子水平上受 TLR4 信号传导调节。基于这些假设，我们将确定 MyD88 和 TRIF 在 HSC 和 Kupffer 细胞之间的独特作用，以及 HSC 中 TLR4 依赖性受体相关信号复合物的作用（目标 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（目标 2）。此外，我们将探讨 TLR4 诱导的趋化因子在肝纤维化中的作用（目标 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提供一种针对TLR4信号传导的新型治疗方法来预防和治疗肝纤维化。