Host protective immune functions of Stabilin receptors in liver

肝脏稳定蛋白受体的宿主保护性免疫功能

• 批准号: 10794490
• 负责人: Latha Prabha Ganesan
• 金额: $ 37.26万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794490
• 关键词: Affect; Alzheimer' s Disease; Atherosclerosis; Binding; Biochemical; Blood Circulation; Breeding; CD14 Antigen; Cell Wall; Cell membrane; Cells; Cessation of life; Chronic Kidney Failure; Circulation; Clathrin; Complex; Crohn' s disease; Cytoprotection; Data; Diabetes Mellitus; Disease; Endocytosis; Endothelial Cells; Endotoxemia; Endotoxins; Future; High Density Lipoproteins; Host Defense; Host Defense Mechanism; Human; Immune; Immunologic Receptors; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intracellular Transport; Knockout Mice; Knowledge; Kupffer Cells; Life; Ligands; Lipopolysaccharides; Literature; Liver; Lysosomes; Mediating; Molecular; Mus; Myelogenous; Organ; Pathway interactions; Patients; Plasma; Play; Process; Production; Publishing; Reaction; Role; Sepsis; Signal Pathway; Sorting; System; TLR4 gene; Testing; Therapeutic; Transgenic Mice; Up-Regulation; autism spectrum disorder; cell type; congenital heart disorder; cytokine; immune function; in vitro Model; in vivo; in vivo Model; innate immune function; insight; liver function; microbial; mortality; mortality risk; novel; novel therapeutics; overexpression; prevent; receptor; receptor mediated endocytosis; receptor-mediated signaling; response; systemic inflammatory response; therapeutic development; therapeutic target; trafficking; uptake

Project Summary or Abstract: Identifying the innate immune receptor and the molecular mechanism involved in rapid clearance of circulating blood-borne Lipopolysaccharide (LPS) will provide critical insights to develop therapeutic options for endotoxe- mia and several LPS-associated diseases. LPS, a major constituent of Gram-negative bacterial cell wall, is a potent microbial ligand that induces intense systemic inflammation via Toll-like receptor 4 (TLR4) in immune cells. LPS in blood circulation (endotoxemia) affects multiple organs and can cause life-threatening inflamma- tory reactions. As a proactive host defense mechanism, the liver clears LPS from blood circulation. However, the mechanisms of the immune cells and associated receptors involved in this process, and whether clearance of LPS overturns TLR4 mediated systemic inflammation, is unknown. In this proposal, we present four remarkably novel findings. First, we found that liver sinusoidal endothelial cells (LSEC) eliminate a major portion of LPS from blood circulation very rapidly within a few minutes, and that clearance of LPS is facilitated by high density lipoprotein (HDL). Secondly, LSEC clear circulating LPS-HDL via Stabilin-1 (Stab1) and Stabilin-2 (Stab2) receptor mediated endocytosis and localize to lysosomes for deg- radation. Third, the lack of both Stab1 and Stab2 in Stabilin double knock out mice results in diminished clear- ance, liver uptake and endocytosis by LSEC, but escalated systemic inflammation and early death in response to LPS. Fourth, Stab1, and to a lesser extent Stab2, participates in host defense. Fifth, Stabilin and TLR4 are functionally opposite receptors for LPS. These results lead us to hypothesize that Stabilin receptors expressed in LSEC offer innate host defense function by decreasing the plasma LPS level and subsequent systemic in- flammation by TLR4. We will test the hypothesis in three major specific aims. In Aim 1, we will determine the mechanism of LPS endocytosis by Stabilin receptors in LSEC, especially the mode of vesicular endocytic traf- ficking in the plasma membrane, the intra-cellular pathways leading to lysosomes for LPS inactivation and deg- radation, and relates the function of Stabilin receptors in LSEC and KC. In Aim 2, we will relate the expression and function of Stabilin receptors with TLR4 in LSEC to clear and endocytose LPS and regulate inflammation in both murine and human LSEC. In Aim 3, we will determine how enhancement of the endocytic function of LSEC decreases the presence of LPS in blood circulation and as a result, controls systemic inflammation. We propose that upregulation of the clearance function of LSEC can be an efficient way to control inflammation during LPS-associated diseases. This project presents a new paradigm in which LSEC and Stabilin receptors offer a host defense mechanism and protection against LPS induced inflammation during various LPS- associated diseases, and points to a novel target for future therapies that treat endotoxemia.

项目摘要或摘要： 鉴定先天免疫受体和涉及快速清除循环的分子机制 血源性脂多糖（LPS）将提供关键的见解，以开发内毒素的治疗选择 - MIA和几种与LPS相关的疾病。 LPS是革兰氏阴性细菌细胞壁的主要成分，是一个 有效的微生物配体，可通过Toll样受体4（TLR4）在免疫中诱导强烈的全身炎症 细胞。血液循环中的LP（内毒素血症）会影响多个器官，并可能导致威胁生命的炎症 保守党反应。作为一种主动的宿主防御机制，肝脏可清除LPS血液循环。然而， 免疫细胞和相关受体参与此过程的机制，以及清除是否 LPS倾覆TLR4介导的全身性炎症是未知的。 在此提案中，我们提出了四个非常新颖的发现。首先，我们发现肝窦内皮 细胞（LSEC）在几分钟内非常迅速地从血液循环中消除了大部分LP，并且 LPS的清除是通过高密度脂蛋白（HDL）促进的。其次，LSEC透明循环LPS-HDL 通过稳定蛋白-1（Stab1）和稳定蛋白-2（Stab2）受体介导的内吞作用，并定位于Deg-的溶酶体 辐射。第三，稳定蛋白双重敲除小鼠的stab1和stab2缺乏，导致清晰度下降 - LSEC的ANCE，肝摄取和内吞作用 到唱片。第四，Stab1，并且在较小程度上Stab2参与了宿主防御。第五，稳定蛋白和TLR4是 LPS功能相反的受体。这些结果使我们假设稳定蛋白受体表达 在LSEC中 TLR4的燃烧。我们将以三个主要的特定目的检验该假设。在AIM 1中，我们将确定 LSEC中稳定蛋白受体的LPS内吞作用的机理，尤其是水泡内吞作用的模式 在质膜中弥补的斑点，细胞内途径导致LPS失活和DEG的溶酶体 辐射，并关联LSEC和KC中稳定蛋白受体的功能。在AIM 2中，我们将联系表达 LSEC中TLR4稳定蛋白受体的功能以及清除和内吞LPS并调节炎症 在鼠和人类LSEC中。在AIM 3中，我们将确定如何增强内吞作用的功能 LSEC降低了血液循环中LPS的存在，因此控制了全身炎症。我们 提出LSEC清除功能的上调可能是控制炎症的有效方法 在LPS相关疾病期间。该项目提出了一个新的范式，其中LSEC和稳定蛋白受体 在各种LPS期间提供宿主防御机制和针对LPS引起的炎症的保护 相关疾病，并指出了治疗内毒素血症的未来疗法的新靶标。