title: PKC-δ activation in neutrophils promotes fungal clearance.
abstract: The C-type lectin receptor dectin-1 and the integrin Mac-1 have key roles in controlling fungal infection. Here, we demonstrate that dectin-1- and Mac-1-induced activation of protein kinase Cδ in neutrophils, independent of the Card9 adaptor, is required for reactive oxygen species production and for intracellular killing upon Candida albicans uptake. Protein kinase Cδ was also required for zymosan-induced cytokine generation in neutrophils. In macrophages, protein kinase Cδ deficiency prevented fungi-induced reactive oxygen species generation but had no effect on activation of TGF-β-activated kinase-1, an effector of Card9, or nuclear factor κB activation, nor did it affect phagolysosomal maturation, autophagy, or intracellular C. albicans killing. In vivo, protein kinase Cδ-deficient mice were highly susceptible to C. albicans and Aspergillus fumigatus infection, which was partially rescued with adoptively transferred wild-type neutrophils. Thus, protein kinase Cδ activation downstream of dectin-1 and Mac-1 has an important role in neutrophil, but not macrophage, functions required for host defense against fungal pathogens.
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Laboratory Medicine, The First Affiliated Hospital, Medical College of Xiamen University, Xiamen, Fujian, China;
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Xavier
authors.initials: X
authors.lastname: Cullere
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishi
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Gurpanna
authors.initials: G
authors.lastname: Saggu
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Enrique
authors.initials: E
authors.lastname: Durand
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; and.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Mansour
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; and.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Tam
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital, Medical College of Xiamen University, Xiamen, Fujian, China;
authors.forename: Xiu-Yu
authors.initials: XY
authors.lastname: Song
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; and.
authors.forename: Jatin M
authors.initials: JM
authors.lastname: Vyas
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; tmayadas@rics.bwh.harvard.edu.
authors.forename: Tanya
authors.initials: T
authors.lastname: Mayadas
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D037181:Lectins, C-Type / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis; D051745:Protein Kinase C-delta / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D051745:Protein Kinase C-delta; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D000099181:Dectin-1; C513280:Card9 protein, mouse; C497259:Prkcd protein, mouse
keywords: C. albicans; Mac-1; dectin-1; host defense; reactive oxygen species; signaling