Abstract
Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1β, and tumor necrosis factor alpha (TNF-α). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aspergillus flavus / pathogenicity
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Aspergillus fumigatus / pathogenicity
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Bacterial Load / immunology
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Candida albicans / pathogenicity
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Down-Regulation
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Enzyme Activation
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Escherichia / pathogenicity
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Inflammation / immunology*
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Interleukin-1 Receptor-Associated Kinases / biosynthesis
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Interleukin-12 / biosynthesis
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Interleukin-1beta / biosynthesis
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Intracellular Signaling Peptides and Proteins / metabolism
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Klebsiella / pathogenicity
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Lectins, C-Type / immunology*
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Macrophages / immunology*
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Mycobacterium / pathogenicity
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Myeloid Differentiation Factor 88 / biosynthesis
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Protein Inhibitors of Activated STAT / biosynthesis
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Protein-Tyrosine Kinases / metabolism
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Reactive Oxygen Species / metabolism
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Staphylococcus / pathogenicity
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / biosynthesis
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Syk Kinase
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Toll-Like Receptors / immunology*
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Tumor Necrosis Factor-alpha / biosynthesis
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Wnt Proteins / biosynthesis
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Wnt Signaling Pathway / immunology*
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Wnt-5a Protein
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beta Catenin / immunology
Substances
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IL1B protein, mouse
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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Lectins, C-Type
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Pias1 protein, mouse
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Protein Inhibitors of Activated STAT
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Reactive Oxygen Species
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Socs1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Wnt Proteins
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Wnt-5a Protein
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Wnt5a protein, mouse
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beta Catenin
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dectin 1
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Interleukin-12
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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Interleukin-1 Receptor-Associated Kinases
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Irak1 protein, mouse
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Irak4 protein, mouse