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： 识别先天免疫受体和快速清除循环中涉及的分子机制 血源性脂多糖（LPS）将为开发内毒素治疗方案提供重要见解 mia 和几种 LPS 相关疾病。 LPS是革兰氏阴性细菌细胞壁的主要成分 有效的微生物配体，通过免疫中的 Toll 样受体 4 (TLR4) 诱导强烈的全身炎症 细胞。血液循环中的脂多糖（内毒素血症）会影响多个器官，并可能导致危及生命的炎症 保守党的反应。作为一种主动的宿主防御机制，肝脏清除血液循环中的脂多糖。然而， 参与该过程的免疫细胞和相关受体的机制，以及清除是否 LPS 能否逆转 TLR4 介导的全身炎症尚不清楚。 在这项提案中，我们提出了四项非常新颖的发现。首先，我们发现肝窦内皮细胞 细胞（LSEC）在几分钟内非常迅速地从血液循环中消除大部分 LPS，并且 高密度脂蛋白 (HDL) 促进 LPS 的清除。其次，LSEC清除循环LPS-HDL 通过 Stabilin-1 (Stab1) 和 Stabilin-2 (Stab2) 受体介导的内吞作用并定位至溶酶体 辐射。第三，Stabilin 双基因敲除小鼠中 Stab1 和 Stab2 的缺失导致清除能力下降。 LSEC 导致肝脏摄取和内吞作用，但导致全身炎症升级并导致早期死亡 至脂多糖。第四，Stab1 以及较小程度上的 Stab2 参与宿主防御。五、Stabilin和TLR4 LPS 功能相反的受体。这些结果使我们推测稳定蛋白受体表达 LSEC 通过降低血浆 LPS 水平和随后的全身感染来提供先天宿主防御功能 TLR4 引起的炎症。我们将在三个主要具体目标上检验这一假设。在目标 1 中，我们将确定 LSEC中Stabilin受体对LPS的内吞机制，特别是囊泡内吞运输的模式 在质膜中，细胞内途径通向溶酶体以进行 LPS 失活和脱除 辐射，并涉及 LSEC 和 KC 中 Stabilin 受体的功能。在目标 2 中，我们将关联表达式 LSEC 中 Stabilin 受体与 TLR4 清除和内吞 LPS 以及调节炎症的功能 在小鼠和人类 LSEC 中。在目标 3 中，我们将确定如何增强内吞功能 LSEC 减少血液循环中 LPS 的存在，从而控制全身炎症。我们 提出上调 LSEC 的清除功能可能是控制炎症的有效方法 在 LPS 相关疾病期间。该项目提出了一种新的范例，其中 LSEC 和 Stabilin 受体 提供宿主防御机制并针对各种 LPS 诱导的炎症提供保护 相关疾病，并为未来治疗内毒素血症的疗法指出了一个新靶标。