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

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对微生物感染的免疫是必不可少的，但在炎症反应和自身免疫病理过程中也可能导致组织损伤。这项应用的总体目标是继续扩大我们对吞噬细胞细胞毒性的分子基础的理解，重点放在吞噬细胞上的两个主要调理受体Fc？RS(免疫球蛋白免疫复合物受体)和整合素Mac-1(补体片段IC3b受体)。过去四年的主要成就是：1)证明了Rho GTP酶家族成员的交换因子Vav蛋白是几种Mac-1和Fc？R介导的中性粒细胞黏附功能所必需的；2)通过调节Rac GTP酶和NADPH氧化酶p40Phox的磷酸化，确定Vav蛋白是Fc？R参与后NADPH氧化酶激活的主要信号转导；3)体内证据表明，中性粒细胞Fc？R依赖而不是补体依赖的组织损伤需要Vav和Rac蛋白，4)Mac-1通过激活src和syk激酶，在体内确定了触发中性粒细胞弹性蛋白酶释放和随后的出血性血管炎的作用。5)在大疱性类天疱疮和血栓性肾小球肾炎这两种补体依赖模型中，Mac-1在中性粒细胞上发挥重要作用。当前的应用程序建立在这些发现的基础上。目的I的目的是描述与补体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。特别是，我们将研究导致其靶标与Mac-1结合的信号以及那些将Mac-1与下游效应器功能联系起来的信号。在AIM II中，我们将进一步阐明Vav介导的Fc？R参与中性粒细胞和巨噬细胞后NADPH氧化酶的调节机制。我们还将在自身免疫性溶血性贫血模型中阐明Vav和Rac在免疫球蛋白或补体介导的巨噬细胞吞噬中的作用。我们预计，我们的目标的完成应该会导致更好地理解将光学受体与特定的吞噬细胞细胞毒功能联系起来的信号通路。这可能有助于治疗药物的设计，以选择性地针对炎症和自身免疫疾病中负责组织损伤的途径，同时将对宿主防御的影响降至最低。

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.