Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and Candida stimulation
Giang T. Nguyen,
Shuying Xu,
Walter Adams,
John M. Leong,
Stephen C. Bunnell,
Michael K. Mansour,
David B. Sykes,
Joan Mecsas
Affiliations
Giang T. Nguyen
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA
Shuying Xu
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA
Walter Adams
Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, MA 02111, USA
John M. Leong
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA; Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, MA 02111, USA
Stephen C. Bunnell
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA; Department of Immunology, School of Medicine, Tufts University, Boston, MA 02111, USA
Michael K. Mansour
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
David B. Sykes
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02115, USA
Joan Mecsas
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA; Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, MA 02111, USA; Corresponding author
Summary: Signaling cascades converting the recognition of pathogens to efficient inflammatory responses by neutrophils are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following neutrophil stimulation by integrins, formyl peptide receptors, and for host defense against the Gram-negative bacterial pathogens, Klebsiella pneumoniae and Yersinia pseudotuberculosis. Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 in neutrophils is crucial for maximal ROS response to purified C-type lectin receptor agonists and to the fungal pathogens, Candida glabrata and Candida albicans, and for robust killing of C. glabrata. Inside-out signaling to integrin and Syk phosphorylation occurred independently of SKAP2 after Candida infection. However, Pyk2, ERK1/2, and p38 phosphorylation were significantly reduced after infection with C. glabrata and K. pneumoniae in Skap2−/− neutrophils. These data demonstrate the importance of SKAP2 in ROS generation and host defense beyond antibacterial immunity to include CLRs and Candida species.
