Loss of SLP-76 expression within myeloid cells confers resistance to neutrophil-mediated tissue damage while maintaining effective bacterial killing.
The Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is an adaptor molecule critical for immunoreceptor and integrin signaling in multiple hemopoietic lineages. We showed previously that SLP-76 is required for neutrophil function in vitro, including integrin-induced adhesion and production of reactive oxygen intermediates, and to a lesser extent, FcgammaR-induced calcium flux and reactive oxygen intermediate production. It has been difficult to determine whether SLP-76 regulates neutrophil responses in vivo, because Slp-76(-/-) mice exhibit marked defects in thymocyte and vascular development, as well as platelet and mast cell function. To circumvent these issues, we generated mice with targeted loss of SLP-76 expression within myeloid cells. Neutrophils obtained from these animals failed to respond to integrin activation in vitro, similar to Slp-76(-/-) cells. Despite these abnormalities, SLP-76-deficient neutrophils migrated normally in vivo in response to Staphylococcus aureus infection and efficiently cleared micro-organisms. Interestingly, SLP-76-deficient neutrophils did not induce a robust inflammatory response in the localized Shwartzman reaction. Collectively, these data suggest that disruption of integrin signaling via loss of SLP-76 expression differentially impairs neutrophil functions in vivo, with preservation of migration and killing of S. aureus but reduction in LPS-induced tissue damage and vascular injury.
Clemens
Regina A
RA
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Lenox
Laurie E
LE
Kambayashi
Taku
T
Bezman
Natalie
N
Maltzman
Jonathan S
JS
Nichols
Kim E
KE
Koretzky
Gary A
GA
D000038:Abscess / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D019426:Integrases / Q000235:genetics; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012790:Shwartzman Phenomenon / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000276:immunology* / Q000473:pathology; D013211:Staphylococcus aureus
D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; C045073:Cre recombinase; D019426:Integrases