Innate Immune Mechanisms and TLRs in Bacterial Ligand-Induced Arteritis

细菌配体诱发的动脉炎中的先天免疫机制和 TLR

基本信息

批准号：
8214584
负责人：
Moshe Arditi
金额：
$ 39.82万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214584
关键词：
Affect Aneurysm Animals Arterial Injury Arteritis Atherosclerosis B-Lymphocytes Bacterial Antigens Bacterial Infections Blood Vessels Bone Marrow CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cell Wall Cells Child Chimera organism Complex Coronary Coronary artery Data Dendritic Cells Dendritic cell activation Development Disease Goals Hematopoietic Host Defense IL2RA gene ITGAX gene Immune Immune response In Vitro Incidence Infection Inflammation Inflammatory Injection of therapeutic agent Intraperitoneal Injections Knockout Mice Lactobacillus casei Lead Lesion Ligands Light Link Marrow Mediating Mediator of activation protein Modeling Molecular Mucocutaneous Lymph Node Syndrome Mus Myelogenous Natural Immunity Nature Pathogenesis Pathology Patients Play Preventive Process Publishing Receptor Signaling Reporter Reporting Research Rest Role Signal Transduction Site T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TLR2 gene TLR4 gene Takayasu&apos s Arteritis Temporal Arteritis Testing Time Toll-Like Receptor 2 Toll-like receptors Toxin Transgenic Mice Vascular Diseases Vascular Endothelial Cell Vasculitis Wild Type Mouse Work adaptive immunity arterial lesion cell type diphtheria toxin receptor immune activation in vivo innovation insight macrophage microbial mouse model novel novel strategies pathogen prevent promoter public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Cellular and molecular mechanisms mediating inflammatory vascular diseases are not well understood. Our previous work has centered on the role of innate immune signaling via Toll-like receptors (TLRs) in inflammatory diseases such as atherosclerosis and arteritis. We reported that injection of cell wall extracts from L. casei (LCCWE) cause coronary arteritis in mice via a TLR2- and MyD88-dependent mechanism, but cell wall extracts from the closely related species L. paracasei do not. Building on this work, our recent preliminary studies now indicate that LCCWE does not induce coronary arteritis in RAG1-/- mice, which lack both T cells and B cells, but does induce lesions in mice that lack only B cells. These important findings now implicate adaptive immune mechanisms (particularly T cells) in addition to innate immune mechanisms (TLR signaling and dendritic cells [DCs]) in the mechanism of LCCWE-induced immune arteritis. Here we propose studies to elucidate cellular and molecular immune mechanisms contributing to bacterial antigen-induced coronary arteritis in mice. Combining available published data with our recent preliminary studies, we propose studies with 3 Specific Aims to test the hypothesis for an expanded model of arteritis that involves both innate and adaptive immunity, that centrally involves both TLR-2 and MyD88-dependent DC and T cell activation. Aim 1 will determine whether DCs participate in LCCWE-induced coronary arteritis in vivo and will evaluate how TLR signaling in DCs affects development of the pathology. We will quantify mature DCs at sites of coronary arteritis at different times and test whether DCs are essential for development of coronary arteritis by depleting DCs prior to injection of LCCWE using an established transgenic mouse model that produces temporary depletion of CD11c+ DCs (CD11c- DTR-GFP Tg+ mice). We will test whether transgenic mice expressing MyD88 only in CD11c+ DCs (in MyD88-null background) develop LCCWE-induced coronary arteritis. Aim 2 will test whether TLR2- and/or MyD88-dependent signaling in hematopoietic cells, in non-hematopoietic cells, or both are essential for development of bacterial antigen-induced immune arteritis. We will create and test chimeras that express TLR2 or MyD88 only in bone marrow-derived cells or only in the rest of the animal. Aim 3 will examine the role of the T cells and T cell subsets in LCCWE-induced coronary arteritis model using various KO mice. Significance: These studies should provide innovative mechanistic insights into the cellular and molecular underpinnings of various forms of immune-mediated arteritis, including the coronary arteritis seen in children with Kawasaki Disease. PUBLIC HEALTH RELEVANCE: Innate immune responses play a role in Bacterial cell wall extract-induced coronary arteritis in a mouse model. Kawasaki Disease is a vasculitis involving children and results in over 20% incidence of developing coronary arteritis and aneurysms. The role of bacterial infections in vasculitis and immune arteritis and the molecular mechanisms involved in this process are not well-understood. The major goal of this application is to understand the molecular mechanisms and the role of innate and adaptive immunity that explain exactly how certain bacterial infections can lead to immune vasculitis and coronary arteritis using a mouse model. The successful completion of the proposed studies may allow us to develop novel treatment or preventive approaches to infection-mediated development of vasculitis and immune arteritis.

描述（由申请人提供）：介导炎症性血管疾病的细胞和分子机制尚不清楚。我们之前的工作集中于通过 Toll 样受体 (TLR) 传递的先天免疫信号在动脉粥样硬化和动脉炎等炎症性疾病中的作用。我们报道，注射干酪乳杆菌细胞壁提取物 (LCCWE) 通过 TLR2 和 MyD88 依赖性机制引起小鼠冠状动脉炎，但密切相关物种副干酪乳杆菌细胞壁提取物则不会。基于这项工作，我们最近的初步研究表明，LCCWE 不会在同时缺乏 T 细胞和 B 细胞的 RAG1-/- 小鼠中诱发冠状动脉炎，但会在仅缺乏 B 细胞的小鼠中诱发病变。这些重要的发现现在表明，除了先天免疫机制（TLR 信号传导和树突状细胞 [DC]）之外，LCCWE 诱导的免疫动脉炎机制中还存在适应性免疫机制（特别是 T 细胞）。在这里，我们提出研究来阐明导致细菌抗原诱导的小鼠冠状动脉炎的细胞和分子免疫机制。将现有已发表的数据与我们最近的初步研究相结合，我们提出了具有 3 个具体目标的研究，以检验涉及先天性免疫和适应性免疫的动脉炎扩展模型的假设，该模型主要涉及 TLR-2 和 MyD88 依赖性 DC 和 T 细胞激活。目标 1 将确定 DC 是否参与 LCCWE 诱导的体内冠状动脉炎，并将评估 DC 中的 TLR 信号传导如何影响病理学的发展。我们将在不同时间量化冠状动脉炎部位的成熟 DC，并通过在注射 LCCWE 之前消耗 DC，使用已建立的转基因小鼠模型来测试 DC 是否对冠状动脉炎的发展至关重要，该转基因小鼠模型会暂时消耗 CD11c+ DC（CD11c- DTR- GFP Tg+ 小鼠）。我们将测试仅在 CD11c+ DC 中表达 MyD88 的转基因小鼠（在 MyD88 缺失背景中）是否会发展 LCCWE 诱导的冠状动脉炎。目标 2 将测试造血细胞、非造血细胞或两者中的 TLR2 和/或 MyD88 依赖性信号传导是否对于细菌抗原诱导的免疫动脉炎的发展至关重要。我们将创建并测试仅在骨髓来源的细胞或仅在动物的其余部分中表达 TLR2 或 MyD88 的嵌合体。目标 3 将使用各种 KO 小鼠检查 T 细胞和 T 细胞亚群在 LCCWE 诱导的冠状动脉炎模型中的作用。意义：这些研究应该为各种形式的免疫介导的动脉炎的细胞和分子基础提供创新的机制见解，包括川崎病儿童中出现的冠状动脉炎。公共卫生相关性：先天免疫反应在小鼠模型中细菌细胞壁提取物诱导的冠状动脉炎中发挥作用。川崎病是一种涉及儿童的血管炎，导致冠状动脉炎和动脉瘤的发生率超过 20%。细菌感染在血管炎和免疫性动脉炎中的作用以及该过程中涉及的分子机制尚不清楚。该应用的主要目标是了解先天性和适应性免疫的分子机制以及作用，从而使用小鼠模型准确解释某些细菌感染如何导致免疫性血管炎和冠状动脉炎。拟议研究的成功完成可能使我们能够开发新的治疗或预防方法来治疗感染介导的血管炎和免疫性动脉炎的发展。