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Src-family and Syk Tyrosine Kinases are Required for Neutrophil Effector Responses to Infection and Inflammation

  • Author(s): Van Ziffle, Jessica Ann Grant
  • Advisor(s): Lowell, Clifford A
  • et al.
Abstract

Leukocyte specific CD18-integrins are critical in mediating cell recruitment and activation during host defense responses to bacterial infection. The signaling pathways downstream of CD18-integrins are dependent on Src-family kinases, including Hck, Fgr and Lyn, as well as the spleen tyrosine kinase, Syk. In a model of pneumococcal meningitis, deficiency of Hck, Fgr and Lyn results in increased susceptibility, due in part to the reduced ability of deficient neutrophils to phagocytose the bacteria, and undergo respiratory burst. To further investigate the role integrin signaling plays in host defense, we examined the responses of Syk-deficient neutrophils to bacterial challenge with serum-opsonized Staphylococcus aureus and Escherichia coli. Syk-conditional knockout mice lacking this kinase specifically in myeloid cells or just neutrophils were also used to investigate host responses in vivo. Syk-deficient neutrophils manifested impaired exocytosis of secondary and tertiary granules, reduced cytokine release and very poor activation of the NADPH oxidase in response to serum-opsonized S. aureus and E. coli. These functional defects correlated with impaired activation of c-Cbl, Pyk2, Erk1/2 and p38 kinases. Bacterial phagocytosis, NET formation and killing were also reduced in Syk-deficient cells, with a more profound effect following S. aureus challenge. In vivo, loss of Syk in myeloid cells or specifically in neutrophils resulted in reduced clearance of S. aureus following subcutaneous or intra-peritoneal infection, despite normal recruitment of inflammatory cells. These results indicate that loss of Syk kinase-mediated integrin signaling impairs leukocyte activation, leading to reduced host defense responses.

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