Glycosphingolipids mediate pneumocystis cell wall β-glucan activation of the IL-23/IL-17 axis in human dendritic cells

TitleGlycosphingolipids mediate pneumocystis cell wall β-glucan activation of the IL-23/IL-17 axis in human dendritic cells
Publication TypeJournal Article
Year of Publication2012
AuthorsCarmona EM, Kottom TJ, Hebrink DM, Moua T, Singh R-D, Pagano RE, Limper AH
JournalAm J Respir Cell Mol Biol
Volume47
Issue1
Pagination50-9
Date Published2012 Jul
ISSN1535-4989
Keywordsbeta-Glucans, Cell Wall, Cells, Cultured, Dendritic Cells, Glycosphingolipids, Humans, Interleukin-17, Interleukin-23, Interleukin-6, Interleukins, Intracellular Signaling Peptides and Proteins, Lectins, C-Type, Membrane Microdomains, NF-kappa B, Pneumocystis, Pneumonia, Pneumocystis, Protein-Tyrosine Kinases, Signal Transduction, Th1 Cells, Th17 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.

DOI10.1165/rcmb.2011-0159OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID22343219
PubMed Central IDPMC3402796
Grant ListR01-HL55934 / HL / NHLBI NIH HHS / United States
R01-HL62150 / HL / NHLBI NIH HHS / United States