A non-cell autonomous requirement for neutrophil BLT1 in inflammatory arthritis

描述（由申请人提供）：类风湿性关节炎是一种慢性、衰弱性疾病，其特征是关节内白细胞的积累，导致明显的疼痛、破坏和功能丧失。通过过继细胞转移研究，我们发现中性粒细胞上的白三烯B4 （LTB4）受体BLT1是炎症性关节炎小鼠模型疾病的绝对需要。然而，表达BLT1的中性粒细胞的主要致病作用是招募缺乏BLT1的中性粒细胞进入关节，揭示了BLT1趋化受体的一种新的非细胞自主功能，这种功能在炎症性关节炎的发展中具有生物学意义。我们将研究两种可能的机制，通过这一过程白细胞募集到关节可能发生。首先，我们假设BLT1是关节源性抗体定位所必需的。我们将研究这些潜在的机制，使用专门的组织学和放射学技术来观察自身抗体沉积。另外，我们之前发现BLT1是白细胞有效的跨内皮迁移所必需的，因此我们假设，表达BLT1的中性粒细胞的跨内皮迁移可能会改变细胞和细胞外基质屏障，使缺乏BLT1的中性粒细胞从循环中向炎症部位迁移。我们将通过多次体外和体内的跨内皮迁移试验来检验第二种假设。除了测试这两种基于机制的假设外，我们将利用基因组学、蛋白质组学和代谢组学技术来确定中性粒细胞的特异性BLT1激活是否会导致中性粒细胞的独特表达，从而使它们能够招募其他细胞群进入炎性关节炎的关节。这些研究将使我们能够了解BLT1在关节特异性炎症发病机制中的作用，并阐明先前未描述的BLT1对白细胞从循环向炎症部位迁移的影响。类风湿性关节炎是一种慢性、使人衰弱的疾病，影响着世界上1%的人口，其特征是关节内炎症细胞的积累，导致严重的疼痛、破坏和功能丧失。我们研究的目标是了解吸引这些炎症细胞进入关节的特定分子信号，目标是将这些信号作为类风湿性关节炎的治疗方法。

DESCRIPTION (provided by applicant): Rheumatoid arthritis is a chronic, debilitating disease characterized by accumulation of leukocytes within the joints, resulting in significant pain, destruction, and loss of function. Through adoptive cell transfer studies, we have found that the leukotriene B4 (LTB4) receptor BLT1 upon neutrophils is an absolute requirement for disease in a mouse model of inflammatory arthritis. However, the primary pathogenic role of BLT1- expressing neutrophils is to recruit BLT1-deficient neutrophils into the joint, revealing a novel non-cell autonomous function for the BLT1 chemoattractant receptor that is biologically relevant in the development of inflammatory arthritis. We will study two potential mechanisms by which this process of leukocyte recruitment into the joint may occur. First, we hypothesize that BLT1 is necessary for arthritogenic antibody localization in the joints. We will investigate these potential mechanisms using specialized histological and radiologic techniques to visualize autoantibody deposition. Alternatively, we have previously found that BLT1 is needed for efficient leukocyte transendothelial migration, so we hypothesize that transmigrating BLT1-expressing neutrophils may alter cellular and extracellular matrix barriers, allowing BLT1-deficient neutrophils to transmigrate out of the circulation towards sites of inflammation. We will test this second hypothesis through multiple in vitro and in vivo assays of transendothelial migration. In addition to testing these two mechanism-based hypotheses, we will utilize genomic, proteomic, and metabolomic technologies to determine whether specific BLT1 activation of neutrophils results in the unique expression of factors that enable to them to recruit other cell populations into the joint in inflammatory arthritis. These studies will enable us to understand the role of BLT1 in the pathogenesis of joint-specific inflammation as well as elucidate previously undescribed effects of BLT1 upon leukocyte migration out of the circulation towards sites of inflammation. Rheumatoid arthritis is a chronic, debilitating disease affecting 1% of the world's population, characterized by the accumulation of inflammatory cells within the joints that results in significant pain, destruction, and loss of function. The goal of our research is to understand the specific molecular signals that attract these inflammatory cells into the joint, with the goal of targeting these signals as therapies in rheumatoid arthritis.