Macrophages as effectors of autoimmune valvular carditis

巨噬细胞作为自身免疫性瓣膜性心脏病的效应器

基本信息

批准号：
9086419
负责人：
Bryce Binstadt
金额：
$ 37.16万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086419
关键词：
Adult Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigen-Antibody Complex Arthritis Attention Autoantibodies Autoimmune Diseases Autoimmune Process Automobile Driving B-Lymphocytes Biological Models Biology CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Carditis Cell Differentiation process Cell Surface Receptors Cells Chronic Data Deposition Disease Equilibrium Fc Receptor Fibrosis Genes Goals Health Heart Valves Human Immunoglobulin G Infiltration Inflammation Inflammatory Inflammatory Response Injury Integrin alpha4beta1 Interferon Type II Interleukin-1 Interleukin-17 Interleukin-18 K/BxN model Knowledge Lead Lupus Macrophage Activation Mediating Methods Modeling Molecular Morbidity - disease rate Mus Myeloid Cells Pathogenesis Pathology Pathway interactions Patient-Focused Outcomes Patients Phenotype Play Population Production Receptor Signaling Recruitment Activity Rheumatism Rheumatoid Arthritis Role Severities Severity of illness System Systemic Lupus Erythematosus T-Lymphocyte TLR4 gene TNF gene Testing Tissues arginase autoimmune arthritis autoreactivity burden of illness cell type chronic autoimmune disease cytokine improved in vivo insight knockout animal macrophage monocyte mortality mouse model neutrophil novel novel therapeutics receptor systemic autoimmune disease tool

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand how cardiovascular tissues are targeted for attack in the context of systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In this proposal we focus on macrophages, a key inflammatory cell type. Although the presence of macrophages in inflamed cardiovascular tissues in patients with these diseases has long been recognized, the tools to dissect their precise role in disease pathogenesis have only recently been developed. We propose to employ these powerful new tools to study how macrophages contribute to cardiovascular inflammation in the setting of systemic rheumatic diseases. We have recently described the occurrence of cardiac valve inflammation in a mouse model of autoimmune arthritis. Valvular carditis in this model is similar to that seen in rheumatic diseases in humans. The cytokine interleukin-17 (IL-17) and immune complexes interacting with activating Fc receptors are critical for carditis to develop. Importantly, macrophages are the predominant inflammatory cell type in this model. Macrophages are characterized broadly as M1 (classical/pro-inflammatory) or M2 (alternative/anti-inflammatory). Our preliminary data suggest that both of these populations may contribute to valvular carditis. We propose to study essential aspects of macrophage biology in this model system: entry into the cardiovascular tissue, activation, and effector function. First, we will determine how macrophages enter the cardiac valves, focusing on the cell surface receptor VLA-4. Next, we will explore how IL-17, activating Fc receptors and TLR4 drive macrophage activation toward M1 or M2 phenotypes. We will then dissect the relative contributions of the M1 and M2 macrophage populations to disease severity, by interfering with the differentiation of these cell subsets or with their key molecular products. Using recently-developed conditional gene knockout animals in conjunction with more traditional methods will allow us to interrogate the pathogenic mechanisms employed by macrophages in this system. Immune complexes, IL-17, and macrophage infiltration are hallmarks of many human autoimmune diseases. We propose to use our novel animal model system to begin to understand how these molecules and cells interact in vivo to provoke tissue pathology, with specific attention to the cardiac valves. The knowledge that we gain is expected to lead to new therapies to reduce the cardiovascular morbidity and mortality among patients with rheumatoid arthritis, lupus, and related autoimmune conditions.

描述（由申请人提供）：我们的长期目标是了解在系统性自身免疫性疾病（如类风湿关节炎和全身性狼疮红膜）的背景下，心血管组织的目标是攻击。在此提案中，我们专注于巨噬细胞，这是一种关键的炎症细胞类型。尽管长期以来已经确认了这些疾病患者的巨噬细胞在发炎的心血管组织中存在巨噬细胞，但直到最近才开发出其在疾病发病机理中进行精确作用的工具。我们建议使用这些强大的新工具来研究巨噬细胞在系统性风湿病的情况下如何促进心血管炎症。我们最近描述了自身免疫性关节炎小鼠模型中心瓣炎症的发生。该模型中的瓣膜性心炎与人类风湿病中所见。细胞因子白介素17（IL-17）和与激活FC受体相互作用的免疫复合物对于心脏炎发育至关重要。重要的是，巨噬细胞是该模型中主要的炎症细胞类型。巨噬细胞的特征是M1（经典/促炎）或M2（替代/抗炎）。我们的初步数据表明，这两个种群都可能导致瓣膜性心脏炎。我们建议在此模型系统中研究巨噬细胞生物学的基本方面：进入心血管组织，激活和效应子功能。首先，我们将确定巨噬细胞如何进入心脏瓣膜，重点是细胞表面受体VLA-4。接下来，我们将探讨IL-17，激活FC受体和TLR4如何将巨噬细胞激活驱动到M1或M2表型。然后，我们将通过干扰这些细胞亚群的分化或其关键分子产物来剖析M1和M2巨噬细胞对疾病严重程度的相对贡献。使用最近开发的条件基因基因敲除动物以及更传统的方法将使我们能够询问该系统中巨噬细胞所采用的致病机制。免疫复合物，IL-17和巨噬细胞浸润是许多人类自身免疫性疾病的标志。我们建议使用新型的动物模型系统开始了解这些分子和细胞如何在体内相互作用以引起组织病理学，并特别注意心脏瓣膜。预计我们获得的知识将导致新的疗法减少类风湿关节炎，狼疮和相关自身免疫性疾病的患者的心血管发病率和死亡率。