Complement Anaphylatoxin Receptors in Inflammation

描述(申请人提供)：补体激活的主要生物学后果之一是产生三个小的阳离子多肽C3a、C4a和C5a，统称为补体过敏毒素。补体过敏性毒素通过与7种表达于特定靶细胞上的跨膜G蛋白偶联受体结合，介导多种生物学功能。C3a和C5a这两种最有效的过敏性毒素的急性和慢性过量生产被认为是许多疾病的主要致病因素，包括类风湿性关节炎、败血症、组织缺血性损伤、急性呼吸窘迫综合征、多系统器官衰竭和特应性哮喘。补体过敏性毒素由羧基肽酶调节，产生活性低得多的DesArg衍生物，C3adesArg和C5adesArg。历史上，Cpn是一种在血浆中结构性表达的羧肽酶，被认为是补体过敏性毒素的唯一羧肽酶调节因子。最近，另外两种分别在血清和上皮细胞(肺和肾)上表达的羧肽酶CPR和CPM被认为是C3a和C5a的额外羧肽酶调节因子。在过去的几年里，我们实验室以及其他实验室的研究表明，补体过敏性毒素C3a和C5a除了具有传统的炎症特性外，在变态反应性和感染性疾病中也是CD4+Th1和Th2效应器功能的重要调节因子。本研究的目的是加深我们对补体过敏性毒素及其受体在相关传染病的炎症、免疫和T细胞反应中的调节和生物学功能的了解。通过利用我们实验室培育的C3aR、C5aR、Cpn和Cpm基因敲除小鼠，我们提出了以下主要目标：1)描述和评价Cpn、CPR和Cpm在调节由C3a、C5a、缓激肽和其他重要炎症分子介导的生物反应中的整体生理意义；2)描述补体过敏性毒素受体、C3aR和C5aR/CD88调节T细胞效应功能的细胞相互作用和分子机制，这在李斯特菌的发病机制中起重要作用。

DESCRIPTION (provided by applicant): One of the major biological consequences of complement activation is the generation of three small cationic peptides C3a, C4a, and C5a, collectively referred to as complement anaphylatoxins. The complement anaphylatoxins mediate numerous biological functions by binding to seven transmembrane G-protein coupled receptors expressed on specific target cells. The acute and chronic overproduction of the two most potent anaphylatoxins, C3a and C5a, is considered to be a major contributor to the pathogenesis of numerous diseases, including rheumatoid arthritis, sepsis, tissue ischemic injury, acute respiratory distress syndrome, multiple system organ failure, and atopic asthma. The complement anaphylatoxins are regulated by carboxypeptidases, which generate their much less active desArg derivatives, C3adesArg and C5adesArg. Historically, CPN, the carboxypeptidase expressed constitutively in plasma, was thought to be the sole carboxypeptidase regulator of complement anaphylatoxins. Recently, two other carboxypeptidases, CPR and CPM, which are expressed in the serum and on epithelial cells (lung and kidney), respectively, have been proposed as additional carboxypeptidase regulators of C3a and C5a. During the past few years studies in our laboratory as well as in others have revealed that the complement anaphylatoxins C3a and C5a in addition to their traditional phlogistic properties are significant modulators of CD4+ Th1 and Th2 effector functions in allergic and infectious disease. The goal of this research program is to increase our understanding of the regulation and biological functions that the complement anaphylatoxins and their receptors mediate in inflammation, immunity, and T cell responses in relevant infectious diseases. By employing C3aR, C5aR, CPN, and CPM "knock-out" mice generated in our laboratory, we propose to major goals: 1) to delineate and evaluate the overall physiological significance of CPN, CPR, and CPM in regulating biological responses mediated by C3a, C5a, bradykinin, and other important inflammatory molecules, and 2) delineate cellular interactions and molecular mechanisms by which the complement anaphylatoxin receptors, C3aR and C5aR/CD88 modulate T-cell effector functions, which are important in the pathogenesis of Listeria monocytogenes.