TY - JOUR
T1 - Interleukin-1 and interferon-γ orchestrate β-glucan-activated human dendritic cell programming via IκB-ζ modulation
AU - Cardone, Marco
AU - Dzutsev, Amiran K.
AU - Li, Hongchuan
AU - Riteau, Nicolas
AU - Gerosa, Franca
AU - Shenderov, Kevin
AU - Winkler-Pickett, Robin
AU - Provezza, Lisa
AU - Riboldi, Elena
AU - Leighty, Robert M.
AU - Orr, Selinda J.
AU - Steinhagen, Folkert
AU - Wewers, Mark D.
AU - Sher, Alan
AU - Anderson, Stephen K.
AU - Goldszmid, Romina
AU - McVicar, Daniel W.
AU - Lyakh, Lyudmila
AU - Trinchieri, Giorgio
N1 - Funding Information:
All of the authors have declared that no competing interests exist. Coauthors Amiran K. Dzutsev and Hongchuan Li are employed by Leidos Biomedical Research, Inc. and Robert M. Leighty by Data Management Services, Inc. They work under contract from the Cancer Research Center, NCI, NIH. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
PY - 2014/12/4
Y1 - 2014/12/4
N2 - Recognition of microbial components via innate receptors including the C-type lectin receptor Dectin-1, together with the inflammatory environment, programs dendritic cells (DCs) to orchestrate the magnitude and type of adaptive immune responses. The exposure to β-glucan, a known Dectin-1 agonist and component of fungi, yeasts, and certain immune support supplements, activates DCs to induce T helper (Th)17 cells that are essential against fungal pathogens and extracellular bacteria but may trigger inflammatory pathology or autoimmune diseases. However, the exact mechanisms of DC programming by β-glucan have not yet been fully elucidated. Using a gene expression/perturbation approach, we demonstrate that in human DCs β-glucan transcriptionally activates via an interleukin (IL)-1-and inflammasome-mediated positive feedback late-induced genes that bridge innate and adaptive immunity. We report that in addition to its known ability to directly prime Tcells toward the Th17 lineage, IL-1 by promoting the transcriptional cofactor inhibitor of κB-ζ (IκB-ζ) also programs β-glucan-exposed DCs to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors. Interferon (IFN)-γ interferes with the IL-1/IκB-ζ axis in β-glucan-activated DCs and promotes T cell-mediated immune responses with increased release of IFN-γ and IL-22, and diminished production of IL-17. Thus, our results identify IL-1 and IFN-γ as regulators of DC programming by β-glucan. These molecular networks provide new insights into the regulation of the Th17 response as well as new targets for the modulation of immune responses to β-glucan-containing microorganisms.
AB - Recognition of microbial components via innate receptors including the C-type lectin receptor Dectin-1, together with the inflammatory environment, programs dendritic cells (DCs) to orchestrate the magnitude and type of adaptive immune responses. The exposure to β-glucan, a known Dectin-1 agonist and component of fungi, yeasts, and certain immune support supplements, activates DCs to induce T helper (Th)17 cells that are essential against fungal pathogens and extracellular bacteria but may trigger inflammatory pathology or autoimmune diseases. However, the exact mechanisms of DC programming by β-glucan have not yet been fully elucidated. Using a gene expression/perturbation approach, we demonstrate that in human DCs β-glucan transcriptionally activates via an interleukin (IL)-1-and inflammasome-mediated positive feedback late-induced genes that bridge innate and adaptive immunity. We report that in addition to its known ability to directly prime Tcells toward the Th17 lineage, IL-1 by promoting the transcriptional cofactor inhibitor of κB-ζ (IκB-ζ) also programs β-glucan-exposed DCs to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors. Interferon (IFN)-γ interferes with the IL-1/IκB-ζ axis in β-glucan-activated DCs and promotes T cell-mediated immune responses with increased release of IFN-γ and IL-22, and diminished production of IL-17. Thus, our results identify IL-1 and IFN-γ as regulators of DC programming by β-glucan. These molecular networks provide new insights into the regulation of the Th17 response as well as new targets for the modulation of immune responses to β-glucan-containing microorganisms.
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U2 - 10.1371/journal.pone.0114516
DO - 10.1371/journal.pone.0114516
M3 - Article
C2 - 25474109
AN - SCOPUS:84915819042
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 12
M1 - e114516
ER -