Sequential Control of Neutrophil Recruitment by LTB4 and Other Chemoattractants

LTB4 和其他化学引诱剂对中性粒细胞募集的顺序控制

• 批准号: 7736015
• 负责人: ANDREW D LUSTER
• 金额: $ 44.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736015
• 关键词: Adhesions; Adoptive Cell Transfers; Adoptive Transfer; Affect; Affinity; Antigen-Antibody Complex; Arthritis; Basement membrane; Biological Assay; Blood; Blood Circulation; Blood Vessels; CCR1 gene; Cell Line; Cells; Chemicals; Chemotactic Factors; Chemotaxis; Chronic; Complement; Complement Receptor; Complex; Data; Development; Disease; Endothelium; Family; Funding; G-Protein-Coupled Receptors; Generations; Human; IL8RA gene; IL8RB gene; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Joints; K/BxN model; LTB4R gene; Leukocyte Trafficking; Leukocytes; Leukotriene B4; Leukotriene B4 Receptors; Leukotrienes; Ligands; Lipids; Mediating; Modeling; Mus; Neutrophil Activation; Neutrophil Infiltration; Patients; Pattern; Phase; Play; Population; Process; Production; Proteins; Resistance; Rheumatoid Arthritis; Role; Serum; Serum Proteins; Signal Transduction; Site; Source; Structure; Surface; Synovial Membrane; System; T-Lymphocyte; Testing; Time; Tissues; asthmatic airway; autocrine; base; cell motility; chemokine; chemokine receptor; fMet-Leu-Phe receptor; in vivo; insight; migration; mouse model; neutrophil; novel; public health relevance; receptor; receptor expression; research study; response; trafficking

DESCRIPTION (provided by applicant): Leukocyte recruitment into tissue compartments is a complex process central to all inflammatory responses. This process involves multiple discrete sequential steps that are orchestrated by a diverse array of chemoattractant molecules, including lipid metabolites (e.g., leukotrienes), proteolytic fragments of serum proteins (e.g., complement) or secreted chemotactic cytokines (e.g., chemokines). Though chemically diverse, these chemoattractants all induce cell migration by activating a family of related chemoattractant G protein-coupled receptors (GPCRs). Although these chemoattractants appear to have overlapping functions in vitro, in vivo studies have uncovered a complexity of leukocyte migration control not appreciated by simple in vitro chemotaxis assays. In the prior funding period, we have contributed to this evolving concept by defining the sequential chemoattractant control of effector T cell migration into the asthmatic airway, initially directed by the leukotriene B4 (LTB4) receptor BLT1 and subsequently by chemokine receptors. In this period, we have also discovered that neutrophil synthesis of LTB4 and BLT1-induced neutrophil responses to LTB4 are absolutely required for the development of immune complex-induced inflammatory arthritis. Surprisingly, we found that the primary pathogenic role for this autocrine LTB4-BLT1 loop is to enable neutrophils to enter the joint via other chemoattractant receptors, indicating that different chemoattractants collaborate to mediate different phases of neutrophil recruitment. We have also found that BLT1 signaling in the neutrophil is upstream of IL-1 and chemokine generation, and that the neutrophil is the critical cellular source of IL-1 in immune-complex induced arthritis. Based on these novel findings, the central hypothesis of this renewal application is that multiple chemoattractant receptors cooperate sequentially to direct neutrophil trafficking into the inflamed joint. We describe four phases of neutrophil recruitment into the joint as: Initiation, Amplification, Facilitation, and Progression. We propose that these phases are sequentially controlled by different chemoattractant receptors, including the complement receptor C5aR, the LTB4 receptor BLT1, and the chemokine receptors CCR1 and CXCR2. Specifically, we propose to: (1) determine the mechanism of initial neutrophil recruitment into the joint and activation upstream of BLT1 signaling; (2) determine the role of the inflammasome in BLT1-induced neutrophil IL-1 production in the amplification of neutrophil recruitment and correlate this to human neutrophils isolated from the blood and joints of patients with active rheumatoid arthritis; (3) determine the mechanism by which BLT1 on facilitates leukocyte transendothelial migration; and (4) determine the respective and differential roles of the neutrophil chemokine receptors CCR1, CXCR1, CXCR2, and their chemokine ligands, in the progression of neutrophil accumulation into the inflamed joint. These studies will define the unique and sequential roles of chemoattractant receptors in the control of neutrophil trafficking in inflammatory arthritis. PUBLIC HEALTH RELEVANCE: Many chronic inflammatory diseases arise from the abnormal accumulation of white blood cells in affected tissue, such as the joint in rheumatoid arthritis. White blood cells are drawn into inflamed tissue from the blood by chemical messengers that are released at sites of inflammation. We have identified a protein called BLT1 that is present upon the surface of white blood cells that is a receptor for one of these important messengers, LTB4. We have found that LTB4 signaling through BLT1 is absolutely required for white blood cells to enter inflamed tissue in certain mouse models of disease, most strikingly in a model of inflammatory arthritis. Further understanding of how BLT1 collaborates with other related receptors, such as the chemokine receptors, to mediate these effects is the focus of this proposal, and will allow for the development of new therapies aimed at inhibiting white blood cell recruitment into inflamed tissue. We expect such therapies will be relevant for arthritis as well as many other chronic inflammatory diseases.

描述（由申请方提供）：白细胞募集至组织隔室是所有炎症反应的核心复杂过程。该过程涉及多个离散的连续步骤，这些步骤由多种多样的化学引诱物分子（包括脂质代谢物（例如，白三烯），血清蛋白的蛋白水解片段（例如，补体）或分泌的趋化细胞因子（例如，趋化因子）。虽然化学成分不同，但这些化学引诱物都通过激活相关的化学引诱物G蛋白偶联受体（GPCR）家族来诱导细胞迁移。虽然这些化学引诱物似乎在体外具有重叠的功能，但体内研究已经揭示了白细胞迁移控制的复杂性，这是简单的体外趋化性测定所不能理解的。在之前的资助期间，我们通过定义效应T细胞迁移到哮喘气道的顺序化学引诱物控制，最初由白三烯B4（LTB 4）受体BLT 1指导，随后由趋化因子受体指导，为这一不断发展的概念做出了贡献。在此期间，我们还发现，LTB 4的中性粒细胞合成和BLT 1诱导的中性粒细胞对LTB 4的反应是免疫复合物诱导的炎性关节炎发展所必需的。令人惊讶的是，我们发现这种自分泌LTB 4-BLT 1环的主要致病作用是使中性粒细胞通过其他化学引诱物受体进入关节，这表明不同的化学引诱物合作介导中性粒细胞募集的不同阶段。我们还发现中性粒细胞中的BLT 1信号传导是IL-1和趋化因子产生的上游，并且中性粒细胞是免疫复合物诱导的关节炎中IL-1的关键细胞来源。基于这些新的发现，该更新应用的中心假设是多个化学引诱物受体顺序地合作以引导中性粒细胞运输到发炎的关节中。我们将中性粒细胞募集到关节中的四个阶段描述为：启动、扩增、促进和进展。我们提出，这些阶段依次控制不同的化学引诱物受体，包括补体受体C5 aR，LTB 4受体BLT 1，和趋化因子受体CCR 1和CXCR 2。具体而言，我们建议：（2）确定炎性小体在BLT 1诱导的中性粒细胞IL-1产生中的作用，并将其与从患有活动性类风湿性关节炎的患者的血液和关节中分离的人中性粒细胞相关联;（3）确定BLT 1促进白细胞跨内皮迁移的机制;和（4）确定中性粒细胞趋化因子受体CCR 1、CXCR 1、CXCR 2及其趋化因子配体在中性粒细胞积聚进入发炎关节的进展中的各自和不同的作用。这些研究将确定化学引诱物受体在炎症性关节炎中性粒细胞运输控制中的独特和顺序作用。公共卫生关系：许多慢性炎性疾病是由于白色血细胞在受影响的组织中的异常积累引起的，例如类风湿性关节炎中的关节。白色血细胞通过在炎症部位释放的化学信使从血液中被吸入炎症组织。我们已经确定了一种名为BLT 1的蛋白质，它存在于白色血细胞的表面，是这些重要信使之一LTB 4的受体。我们已经发现，在某些小鼠疾病模型中，白色血细胞进入发炎组织绝对需要通过BLT 1的LTB 4信号传导，在炎症性关节炎模型中最为显著。进一步了解BLT 1如何与其他相关受体，如趋化因子受体，介导这些作用是本提案的重点，并将允许开发旨在抑制白色血细胞募集到炎症组织中的新疗法。我们预计这种疗法将与关节炎以及许多其他慢性炎症性疾病有关。