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 n ecessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after Fc gamma R cross-lin king. Macrophages derived from Syk-deficient (Syk(-)) mice were defect ive in phagocytosis of particles bound by Fc gamma Rs, as well as in m any Fc gamma R-induced signaling events, including tyrosine phosphoryl ation of a number of cellular substrates and activation of MAP kinases . In contrast, Syk(-) macrophages exhibited normal responses to anothe r potent macrophage stimulus, Lipopolysaccharide. Phagocytosis of late x beads and Escherichia coli bacteria was also not affected. Syk(-) ma crophages 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 phosphatid ylinositol 3-kinase also blocked Fc gamma R-mediated phagocytosis at t his stage. Thus, PI 3-kinase may participate in a Syk-dependent signal ing pathway critical for Fc gamma R-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family o f kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon Fc gamma R engagement, accompanied by a delay in F c gamma R-mediated phagocytosis. These observations demonstrate that S yk is critical for Fc gamma R-mediated phagocytosis, as well as for si gnal transduction in macrophages. Additionally, our findings provide e vidence to support a model of. sequential tyrosine kinase activation b y Fc gamma R's analogous to models of signaling by the B and T cell an tigen receptors.