Mac-1 (CR3) and Fc gamma receptors in immune-mediated neutrophil cytotoxicity

Mac-1 (CR3) 和 Fc gamma 受体在免疫介导的中性粒细胞细胞毒性中的作用

基本信息

批准号：
7582061
负责人：
Tanya N Mayadas
金额：
$ 39.37万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7582061
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Adhesives Antibodies Antigen-Antibody Complex Attenuated Autoimmune Diseases Autoimmune Process Autoimmune hemolytic anemia Binding Biochemical Biological Assay Bullous Pemphigoid C3bi Clinical Trials Complement Coupled Cutaneous Involvement Data Deposition Dermal Disease Ensure Erythrocytes Exhibits Family Family member Funding Generations Glomerulonephritis Glucans Goals Grant Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Hemolytic Anemia Hemorrhagic Vasculitis Host Defense Host Defense Mechanism ITAM IgG Receptors Immune Immunity Immunocompromised Host Immunoglobulin G Immunosuppression In Vitro Infection Inflammatory Inflammatory Response Injury Integrins Lead Leukocyte Elastase Link Macrophage-1 Antigen Mediating Modeling Molecular Mycoses Myelogenous NADPH Oxidase Neutrophil Infiltration Organ Pathology Pathway interactions Phagocytes Phagocytosis Phagosomes Pharmaceutical Preparations Phospholipase C Phospholipase D Phosphorylation Phosphotransferases Physiological Play Predisposition Process Protein Family Protein Kinase C Protein Tyrosine Kinase Proteins Proteomics Reactive Oxygen Species Regulation Relative (related person)Respiratory Burst Rheumatism Role Shwartzman Phenomenon Signal Pathway Signal Transduction Signaling Molecule Therapeutic Tissues Transducers Treatment Efficacy Variant Vasculitis base combat comparative cytotoxic cytotoxicity dectin 1 design glomerular basement membrane human SYK protein human disease in vitro Assay in vivo in vivo Model interest macrophage microbial natalizumab neutrophil neutrophil cytosol factor 40K opsonin receptor particle protein function public health relevance rac GTP-Binding Proteins receptor response rho rho GTP-Binding Proteins skin disorder src-Family Kinases therapeutic development therapeutic target tool trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Phagocytic functions of neutrophils and macrophages are essential for immunity to microbial infection, but can also contribute to tissue injury during inflammatory responses and autoimmune pathologies. The overall goal of this application is to continue to extend our understanding of the molecular basis of phagocyte cytotoxicity focusing on two major opsonic receptors on phagocytes, Fc?Rs (receptors for IgG immune complex) and the ¿2 integrin Mac-1 (receptor for complement fragment iC3b). Major accomplishments of the past 4 years were to 1) demonstrate that Vav proteins, exchange factor for Rho GTPase family members are required for several Mac-1 and Fc?R mediated adhesive functions in neutrophils, 2) identify Vav proteins as the major signal transducers of NADPH oxidase activation following Fc?R engagement, through regulation of Rac GTPases and phosphorylation of the NADPH oxidase p40phox, 3) present in vivo evidence that neutrophil Fc?R dependent but not complement dependent tissue injury requires Vav and Rac proteins, 4) define a role for Mac-1 in triggering neutrophil elastase release and subsequent hemorrhagic vasculitis in vivo, through activation of the src and syk kinases, and 5) demonstrate a critical role for Mac-1 on neutrophils in two additional complement dependent models, bullous pemphigoid and thrombotic glomerulonephritis. The current application builds on these discoveries. The objective of Aim I is to delineate mechanisms of neutrophil phagocytosis that are relevant for complement C3 mediated tissue injury and host defense. In particular we will examine both signals that lead to Mac-1 binding of its target and those that link Mac-1 to downstream effector functions. In Aim II, we will further delineate mechanisms of Vav mediated regulation of the NADPH oxidase following Fc?R engagement in neutrophils and macrophages. We will also clarify the role of Vav and Rac in IgG or complement mediated phagocytosis in macrophages in models of autoimmune hemolytic anemia. We anticipate that the completion of our aims should lead to a better understanding of signaling pathways that link opsonic receptors to specific phagocyte cytotoxic functions. This may aid in the design of therapeutics to selectively target pathways responsible for tissue damage in inflammatory and autoimmune disorders while minimizing effects on host defense. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to understand the neutrophil dependent mechanisms that mediate injury to the dermal microvasculature, a well-recognized target of autoimmune damage that contributes to end organ/skin disease. For example, the inflammatory destruction of the vessel wall, vasculitis, is observed in autoimmune rheumatic diseases with cutaneous involvement being the most common, and neutrophil accumulation being a common feature. Drugs such as natalizumab, which interferes with neutrophil trafficking have demonstrated marked therapeutic efficacy in autoimmune diseases, but also exhibited potentially fatal immunosuppression. In this application we propose to delineate signaling pathways that potentially promote microvascular tissue damage, but are not required for neutrophil recruitment. This could lead to the identification of targeted therapeutic strategies that attenuate organ injury while minimally immunocompromising the host.

描述（由申请人提供）：中性粒细胞和巨噬细胞的吞噬功能对于微生物感染的免疫至关重要，但也可能导致炎症反应和自身免疫病理过程中的组织损伤。本申请的总体目标是继续扩展我们对微生物感染的理解。吞噬细胞细胞毒性的分子基础，重点关注吞噬细胞上的两种主要调理受体：Fc?R（IgG 免疫复合物的受体）和 ¿ 2 整合素 Mac-1（补体片段 iC3b 的受体）过去 4 年的主要成就是 1) 证明 Vav 蛋白（Rho GTPase 家族成员的交换因子）是多种 Mac-1 和 Fc?R 介导的粘附功能所必需的。在中性粒细胞中，2) 通过调节 Rac GTPases 和 Fc?R 接合，确定 Vav 蛋白是 Fc?R 参与后 NADPH 氧化酶激活的主要信号转导子NADPH 氧化酶 p40phox 的磷酸化，3) 体内证据表明中性粒细胞 Fc?R 依赖性而非补体依赖性组织损伤需要 Vav 和 Rac 蛋白，4) 定义了 Mac-1 在触发中性粒细胞弹性蛋白酶释放和随后的出血性血管炎中的作用体内，通过激活 src 和 syk 激酶，5) 证明 Mac-1 对中性粒细胞的关键作用两个额外的补体依赖性模型，大疱性类天疱疮和血栓性肾小球肾炎当前的应用建立在这些发现的基础上，目的是描述与补体 C3 介导的组织损伤和宿主防御相关的中性粒细胞吞噬机制。导致 Mac-1 与其靶标结合的信号以及将 Mac-1 与下游效应器功能联系起来的信号。在 Aim II 中，我们将进一步描述 Vav 的机制。我们还将阐明 Vav 和 Rac 在自身免疫性溶血性贫血模型中巨噬细胞中 IgG 或补体介导的吞噬作用中的作用。导致更好地理解将调理受体与特定吞噬细胞细胞毒性功能联系起来的信号通路，这可能有助于设计选择性靶向通路的治疗方法。负责炎症和自身免疫性疾病中的组织损伤，同时最大限度地减少对宿主防御的影响。公共健康相关性：本提案的目的是了解介导真皮微脉管系统损伤的中性粒细胞依赖性机制，真皮微脉管系统是公认的导致终末器官/皮肤疾病的自身免疫损伤的目标，例如血管的炎症破坏。血管壁炎，血管炎，常见于自身免疫性风湿性疾病，其中皮肤受累是最常见的，中性粒细胞积聚是常见特征，例如药物。那他珠单抗干扰中性粒细胞运输，在自身免疫性疾病中具有显着的治疗功效，但也表现出潜在的致命性免疫抑制作用。在本申请中，我们建议描绘出可能促进微血管组织损伤的信号通路，但这些信号通路对于中性粒细胞募集来说不是必需的。确定有针对性的治疗策略，以减轻器官损伤，同时最大限度地减少宿主的免疫功能受损。