The Syk Protein Tyrosine Kinase Is Essential for Fcγ Receptor Signaling in Macrophages and Neutrophils

ABSTRACT

The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcγ receptor (FcγR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk^−/− embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcγR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcγR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcγR γ chain, as well as Erk2 activation, was compromised in Syk ^−/− macrophages after FcγR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcγRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.

ACKNOWLEDGMENTS

We thank Marie-Helen Jouvin and Bruce Rowley for generously providing γ-chain and Syk antibodies. We thank Matthias Clauss and Werner Risau, Bad Nauheim, Germany, for helpful discussions. We thank Ken Harpal for excellent help with histology.

N.A.-A. was supported by a Terry Fox postdoctoral fellowship from the National Cancer Institute of Canada. J.B. is the recipient of a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada. This work was supported by grants from Bristol-Meyers-Squibb, the Medical Research Council of Canada, and the National Cancer Institute of Canada to T.P. and from the Medical Research Council of Canada to S.G. T.P. and S.G. are International Research Scholars of the Howard Hughes Medical Institute. T.P. is a Terry Fox Cancer Research Scientist of the National Cancer Institute of Canada.