Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection.
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 the spleen tyrosine kinase, Syk. To 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, neutrophil extracellular trap formation, and killing were also reduced in Syk-deficient cells, with a more profound effect after S aureus challenge. In vivo, loss of Syk in myeloid cells or specifically in neutrophils resulted in reduced clearance of S aureus after subcutaneous or intraperitoneal 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.
Immunology Program and the Department of Laboratory Medicine, University of California-San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0451, USA.
Jessica A
JA
Van Ziffle
Clifford A
CA
Lowell
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D018821:CD18 Antigens / Q000276:immunology; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D004927:Escherichia coli Infections / Q000201:enzymology / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology* / Q000502:physiology; D009895:Opsonin Proteins / Q000276:immunology; D010587:Phagocytosis; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000502:physiology; D016897:Respiratory Burst; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000201:enzymology* / Q000276:immunology; D000072377:Syk Kinase
D018821:CD18 Antigens; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D009895:Opsonin Proteins; D019255:NADPH Oxidases; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse