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

炎症性关节炎对中性粒细胞 BLT1 的非细胞自主需求

基本信息

批准号：
7812130
负责人：
NANCY D KIM
金额：
$ 13.05万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-21 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7812130
关键词：
Adhesions Adoptive Cell Transfers Adoptive Transfer Affect Antibodies Applications Grants Arthritis Attenuated Autoantibodies Basement membrane Biological Biological Assay Blood Circulation Blood Vessels Cell Line Cells Chronic Complex Cytoplasmic Granules Deposition Development Disease Enabling Factors Endothelium Environment Enzymes Extracellular Matrix Flow Cytometry Generations Genetic Transcription Genomics Glucosephosphate Isomerase Goals Hour Human Immunoglobulin G In Vitro Inflammation Inflammatory Injection of therapeutic agent Joints K/BxN model LTB4R gene Laboratories Leukocytes Leukotriene B4 Leukotriene B4 Receptors Longevity Mediating Mediator of activation protein Modeling Molecular Mus Natural Immunity Neutrophil Activation Neutrophil Infiltration Out-Migrations Oxygen Pain Pathogenesis Peptide Hydrolases Peripheral Phenotype Play Polyarthritides Population Process Property Proteomics Recruitment Activity Research Research Personnel Rheumatoid Arthritis Role Serum Signal Transduction Simulate Site Staging Structure Synovial Fluid Techniques Technology Testing Tissues Wild Type Mouse analytical method base chemokine cytokine fMet-Leu-Phe receptor in vitro Model in vivo lipid mediator loss of function mast cell metabolomics migration mouse model neutrophil novel programs receptor response trafficking

项目摘要

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.

描述(申请人提供)：类风湿性关节炎是一种慢性衰弱疾病，其特征是白细胞在关节内积聚，导致严重的疼痛、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要求。然而，表达BLT1的中性粒细胞的主要致病作用是将缺乏BLT1的中性粒细胞招募到关节中，揭示了BLT1趋化因子受体的一种新的非细胞自主功能，该功能在炎性关节炎的发生发展中具有生物学意义。我们将研究这一白细胞重新进入关节的过程可能发生的两种潜在机制。首先，我们假设BLT1是关节致炎抗体定位所必需的。我们将使用专门的组织学和放射学技术来研究这些潜在的机制，以可视化自身抗体的沉积。或者，我们先前发现BLT1是白细胞有效地跨内皮细胞迁移所必需的，因此我们假设，迁移表达BLT1的中性粒细胞可能会改变细胞和细胞外基质屏障，允许缺乏BLT1的中性粒细胞向炎症部位转移。我们将通过多个体外和体内跨内皮细胞迁移的测试来验证第二个假设。除了测试这两个基于机制的假说，我们还将利用基因组、蛋白质组和代谢组学技术来确定中性粒细胞的BLT1特异性激活是否导致因子的独特表达，使它们能够在炎症性关节炎中招募其他细胞群到关节中。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，以及阐明BLT1对白细胞从循环向炎症部位迁移的先前未被描述的作用。类风湿性关节炎是一种慢性、衰弱的疾病，影响着世界1%的人口，其特征是关节内炎症细胞的聚集，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，目的是将这些信号作为治疗类风湿性关节炎的靶向。