title: Glycosphingolipids mediate pneumocystis cell wall β-glucan activation of the IL-23/IL-17 axis in human dendritic cells.
abstract: Pneumocystis species are opportunistic fungal organisms that cause severe pneumonia in immune-compromised hosts, with resultant high morbidity and mortality. Recent work indicates that IL-17 responses are important components of host defense against fungal pathogens. In the present study, we demonstrate that cell-surface β-glucan components of Pneumocystis (PCBG) stimulate human dendritic cells (DCs) to secrete IL-23 and IL-6. These cytokines are well established to stimulate a T helper-17 (Th17) phenotype. Accordingly, we further observe that PCBG-stimulated human DCs interact with lymphocytes to drive the secretion of IL-17 and IL-22, both Th17-produced cytokines. The activation of DCs was shown to involve the dectin-1 receptor with a downstream activation of the Syk kinase and subsequent translocation of both the canonical and noncanonical components of the NF-κB transcription factor family. Finally, we demonstrate that glycosphingolipid-rich microdomains of the plasma membrane participate in the activation of DCs by PCBG through the accumulation of lactosylceramide at the cell surface during stimulation with PCBG. These data strongly support the idea that the β-glucan surface components of Pneumocystis drive the activation of the IL-23/IL-17 axis during this infection, through a glycosphingolipid-initiated mechanism.
authors.affiliation: Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Department of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Carmona
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Kottom
authors.forename: Deanne M
authors.initials: DM
authors.lastname: Hebrink
authors.forename: Teng
authors.initials: T
authors.lastname: Moua
authors.forename: Raman-Deep
authors.initials: RD
authors.lastname: Singh
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pagano
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Limper
mesh_terms: D002473:Cell Wall / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011010:Pneumocystis / Q000472:pathogenicity*; D011020:Pneumonia, Pneumocystis / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D047071:beta-Glucans / Q000276:immunology*; D000097043:Interleukin-22; D000099181:Dectin-1
chemical_list: D006028:Glycosphingolipids; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D047071:beta-Glucans; D000097043:Interleukin-22; D000099181:Dectin-1; C000606896:SYK protein, human