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* Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Medical Scientist Training Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Division of Oncology, Children’s Hospital of Philadelphia, PA 19104;
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
¶ Graduate Program in Cell and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
|| Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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, Fc
R-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (to R.A.C., L.E.L., T.K., J.S.M., K.E.N., and G.A.K.) and a predoctoral fellowship from the Howard Hughes Medical Institute (to N.B.).
2 Address correspondence and reprint requests to Dr. Gary A. Koretzky, University of Pennsylvania, Biomedical Research Building II/III, Room 416, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail address: koretzky{at}mail.med.upenn.edu
3 Abbreviations used in this paper: ROI, reactive oxygen intermediate; IC, immune complex; PLC, phospholipase C; SLP-76, Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa; GPVI, glycoprotein VI; PSA, passive systemic anaphylaxis; LSR, localized Shwartzman reaction; WT, wild type; HSA, human serum albumin; PMN, polymorphonuclear neutrophil; BMMC, bone marrow-derived mast cell; BMM, bone marrow-derived macrophage.
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