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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：
8073489
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 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073489
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 Cytoskeleton 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 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（由申请人提供）：风湿性关节炎是一种慢性、使人衰弱的疾病，其特征是关节内白细胞积聚，导致显著疼痛、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BLT 1是炎症性关节炎小鼠模型中疾病的绝对需要。然而，表达BLT1的嗜中性粒细胞的主要致病作用是将BLT1缺陷的嗜中性粒细胞募集到关节中，揭示了BLT1趋化因子受体的一种新的非细胞自主功能，其在炎症性关节炎的发展中具有生物学相关性。我们将研究两种可能的机制，通过这一过程中白细胞招募到关节可能发生。首先，我们假设BLT1对于关节中的致关节炎抗体定位是必要的。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，以可视化自身抗体沉积。或者，我们以前发现，BLT 1是需要有效的白细胞跨内皮迁移，所以我们假设，transmigrating BLT 1表达的中性粒细胞可能会改变细胞和细胞外基质的障碍，使BLT 1缺陷的中性粒细胞transmigrating出循环的炎症部位。我们将通过多种体外和体内跨内皮迁移试验来检验第二种假设。除了测试这两个机制为基础的假设，我们将利用基因组学，蛋白质组学和代谢组学技术，以确定是否特定的BLT1激活中性粒细胞的结果在独特的表达因子，使他们能够招募其他细胞群进入关节炎性关节炎。这些研究将使我们能够了解BLT 1在关节特异性炎症发病机制中的作用，并阐明BLT 1对白细胞从循环中向炎症部位迁移的先前未描述的作用。风湿性关节炎是一种慢性、使人衰弱的疾病，影响世界上1%的人口，其特征在于炎性细胞在关节内积聚，导致显著疼痛、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。