Macrophages as effectors of autoimmune valvular carditis

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（如类风湿性关节炎和系统性红斑狼疮）的背景下，心血管组织是如何被靶向攻击的。在这项提案中，我们专注于巨噬细胞，一种关键的炎症细胞类型。虽然巨噬细胞在这些疾病患者的炎症心血管组织中的存在早已被认识到，但直到最近才开发出剖析其在疾病发病机制中的确切作用的工具。我们建议利用这些强大的新工具来研究巨噬细胞如何在全身性风湿性疾病的背景下促进心血管炎症。我们最近描述了发生心脏瓣膜炎症的小鼠模型的自身免疫性关节炎。该模型中的瓣膜炎与人类风湿性疾病中所见相似。 细胞因子白细胞介素-17（IL-17）和免疫复合物与激活的Fc受体相互作用是心脏炎发生的关键。重要的是，巨噬细胞是该模型中的主要炎性细胞类型。巨噬细胞广泛地表征为M1（经典/促炎）或M2（替代/抗炎）。我们的初步数据表明，这两种人群都可能导致瓣膜性心脏炎。我们建议在这个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，激活和效应器功能。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，我们将探索IL-17、活化Fc受体和TLR 4如何驱动巨噬细胞活化朝向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巨噬细胞群体对疾病严重程度的相对贡献。 使用最近开发的条件性基因敲除动物与更传统的方法相结合，将使我们能够询问该系统中巨噬细胞的致病机制。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。我们建议使用我们的新的动物模型系统，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，特别注意心脏瓣膜。我们获得的知识有望导致新的治疗方法，以减少类风湿性关节炎，狼疮和相关自身免疫性疾病患者的心血管发病率和死亡率。

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.