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：
7463435
负责人：
Moshe Arditi
金额：
$ 40.63万
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 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7463435
关键词：
Affect Aneurysm Animals Appendix 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 Green Fluorescent Proteins Hematopoietic Host Defense ITGAX gene Immune Immune response Immunity In Vitro Incidence Infection Inflammation Inflammatory Injection of therapeutic agent Intraperitoneal Injections Knockout Mice Lactobacillus casei Lead Lesion Ligands Light Link Mediating Mediator of activation protein Modeling Molecular Mucocutaneous Lymph Node Syndrome Mus Myelogenous Nature Numbers Pathogenesis Pathology Patients Play Preventive Process Public Health Publishing Receptor Signaling Reporter Reporting Research Rest Role Signal Transduction Site 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 Transgenic Organisms Vascular Diseases Vascular Endothelial Cell Vasculitis Wild Type Mouse Work arterial lesion cell type concept diphtheria toxin receptor in vivo innovation insight macrophage microbial mouse model novel novel strategies pathogen prevent promoter research study response

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）：介导炎症血管疾病的细胞和分子机制尚不清楚。我们以前的工作集中在炎症性疾病（如动脉粥样硬化和动脉炎）中，通过Toll样受体（TLR）通过Toll样受体（TLR）的作用为重点。我们报道说，从L. casei（LCCWE）中注射细胞壁提取物通过TLR2-和MYD88依赖性机制在小鼠中引起冠状动脉炎，但是来自密切相关的物种L. paracasei的细胞壁提取物没有。在这项工作的基础上，我们最近的初步研究现在表明，LCCWE不会诱导RAG1 - / - 小鼠中缺乏T细胞和B细胞的冠状动脉炎，但确实诱导仅缺乏B细胞的小鼠病变。这些重要发现现在暗示了除先天免疫机制（TLR信号传导和树突状细胞[DCS]）之外的适应性免疫机制（尤其是T细胞）。在这里，我们提出的研究旨在阐明有助于细菌抗原诱导的小鼠冠状动脉炎的细胞和分子免疫机制。将可用的公开数据与我们最近的初步研究相结合，我们提出了3种特定目的研究，以测试涉及先天和适应性免疫的扩展的动脉炎模型的假设，从而集中涉及TLR-2和MYD88依赖性DC和T细胞活化。 AIM 1将确定DC在体内是否参与LCCWE诱导的冠状动脉炎，并评估DC中的TLR信号如何影响病理的发展。我们将在不同时间量化冠状动脉炎部位的成熟DC，并通过使用已建立的转基因小鼠模型在注入LCCWE之前耗尽DC来测试DC是否对冠状动脉炎的发展至关重要，从而产生CD11C+ DCS的临时耗竭（CD11C-DTR-GFP-GFP TG+ MICE）。我们将测试仅在CD11C+ DC中表达MYD88的转基因小鼠（在myd88-null背景中）是否会发展出LCCWE诱导的冠状动脉炎。 AIM 2将测试造血细胞中的TLR2-和/或MYD88依赖性信号传导，非造血细胞中的TLR2-和/或MYD88依赖性信号传导，还是两者对于开发细菌抗原诱导的免疫动脉炎至关重要。我们将创建和测试仅在骨髓衍生的细胞或仅在动物的其余部分中表达TLR2或MYD88的嵌合体。 AIM 3将使用各种KO小鼠研究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理见解，包括在川崎病儿童中看到的冠状动脉炎。公共卫生相关性：先天免疫反应在小鼠模型中的细菌细胞壁提取物诱导的冠状动脉炎中起作用。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发病率超过20％。细菌感染在血管炎和免疫动脉炎以及此过程中涉及的分子机制中的作用并不理解。该应用的主要目的是了解先天和适应性免疫的分子机制和作用，以准确解释某些细菌感染如何使用小鼠模型导致免疫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出新颖的治疗方法或预防方法，以感染介导的血管炎和免疫动脉炎的发育。