Alveolar macrophages (PAM) are the major resident phagocytic cells in the lung and as such they are the initial phagocytic cells involved in the defense of the lung from infection. A major mechanism by which these cells clear microorganisms from the lung is by Fcgamma receptor mediated phagocytosis. When PAM phagocytose IgG-coated cells or ingest immune complexes by their Fcgamma receptors, they can also release reactive intermediates such as superoxide and cytokines which likely play a significant role in the pathogenesis of immune complex mediated lung injury. We have established that all three Fcgamma receptor classes are expressed on PAM and that human Fcgamma receptors of each class can induce phagocytosis in the absence of any other human Fcgamma receptor. Furthermore, we have observed that normally non-phagocytic cells such as bronchial and lung epithelial cells will mediate phagocytosis of IgG coated cells when transfected with an appropriate Fcgamma receptor. We have also determined that one of the key PAM Fcgamma receptors, FcgammaRIIIA, transmits a phagocytic signal through the cytoplasmic domain of an associated gamma subunit, that the cytoplasmic domain of the gamma subunit is necessary for phagocytosis by FcgammaRIIIA and that Syk kinase, associated with the Fcgamma receptor gamma chain in PAM, enhances phagocytosis by FcgammaRIIIA several fold. The central goal of this project is to define the mechanistic properties and functional consequences underlying Fcgamma receptor and Syk kinase interactions in vitro and in vivo. In addressing this goal in the specific aims, our studies will 1) utilize macrophage FcgammaRIIIA receptor transfectants to further study the structure/function relationships of FcgammaRIIIA and its gamma subunit, as well as the requirement for Syk kinase, in signal transduction; 2) utilize biosensor analysis to compare the interaction of Syk with FcgammaRIIIA/gamma and with FcgammaRIIA, another PAM Fcgamma receptor which our data indicate interacts with Syk in a different manner from FcgammaRIIIA/gamma; 3) examine the mechanism of the phagocytic process in Fcgamma receptor transfectants of human bronchial and lung epithelial cells, having observed that Fcgamma receptor transfectants of these normally non-phagocytic cells mediate the phagocytosis of IgG coated cells; and finally, 4) utilize an established animal model to study the in vivo role of Syk kinase in PAM Fcgamma receptor induced mediator release in pulmonary inflammation.
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