Macrophages present in the lung parenchyma and within the airway lumen are critical components of immune complex mediated acute lung injury. Following exposure to immune complexes, macrophages accumulate in the lung and induce the release of cytokines and other biologically active products. These responses are largely initiated by Fcgamma receptors (FcgammaR) on the macrophage surface that interact with IgG containing complexes. Syk kinase plays a critical role in the signaling machinery of FcgammaRs and our studies have demonstrated that targeted disruption of Syk in the lung leads to inhibition of FcgammaR function and thereby to a salutary impact on immune complex induced pulmonary inflammation. Our studies will combine in vitro and in vivo molecular and cell biology approaches to further examine how Syk contributes to IgG mediated lung injury. In as much as Cbl, through its function as a ubiquitin ligase, promotes degradation negative regulation of Syk and modulates the function of a number of receptors, our thesis is that by promoting Syk and/or FcgammaR ubiquitination, Cbl in alveolar macrophages (AM) inhibits the release of inflammatory mediators. For in vivo studies of the effect of Cbl on immune complex mediated lung inflammation, we will utilize Cbl knockout (KO) mice and our unique Cbl KO mice transgenic (TG) for human FcgammaRIIA in an established mouse model of immune complex mediated lung injury. For ex vivo studies, we will determine Fc(R induced mediator re-lease from the AM of these mice. Another aim is based on the relationship of Syk to FcgammaR function and our unexpected observation that PECAM-1 enhances lung FcgammaR mediated PMN influx, TNF release and phagocytosis.
This aim will examine the interaction of PECAM-1 with FcgammaR/Syk in AM. We have available PECAM-1 140 mice and have created PECAM-1 KO mice TG for FcgammaRIIA. In addition, since epithelial cells are considered important in inflammatory disorders, we will build on our observation that bronchial epithelial cells express Syk kinase and explore the role of Syk in the release of inflammatory mediators by lung epithelial cells. Finally, in extension of our novel observation that FcgammaR mediated phagolysosomal fusion (affected by Syk kinase) and its associated calcium signal requires a FcgammaR cytoplasmic sequence distinct from that required for the initial internalization step of phagocytosis, we will examine parameters of phagolysosomal fusion by FcgammaR. Continued progress in understanding the interactions of Fc(Rs and Syk kinase is important for development of new approaches in the treatment of inflammatory/immune complex disorders of the lung.
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