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. ? ? ?
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