A critical role for Syk in signal transduction and phagocytosis mediated by Fc gamma receptors on macrophages

Receptors on macrophages for the Fc region of IgG (Fc gamma R) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after Fc gamma R cross-linking. Macrophages derived from Syk-deficient (Syk(-)) mice were defective in phagocytosis of particles bound by Fc gamma Rs, as well as in many Fc gamma R-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk(-) macrophages exhibited normal responses to another potent macrophage stimulus, Lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk(-) macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by Fc gamma Rs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked Fc gamma R-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for Fc gamma R-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon Fc gamma R engagement, accompanied by a delay in Fc gamma R-mediated phagocytosis. These observations demonstrate that Syk is critical for Fc gamma R-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of. sequential tyrosine kinase activation by Fc gamma R's analogous to models of signaling by the B and T cell antigen receptors.