Abstract
Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS)-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.
Keywords:
C-type lectin receptors; hepatocellular cancer; liver fibrosis.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Transformation, Neoplastic / drug effects
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Cells, Cultured
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Chemokine CCL2 / blood
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Cytokines / metabolism
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Diethylnitrosamine / toxicity
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Hepatocytes / cytology
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Hepatocytes / metabolism
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Humans
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Inflammation
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Lectins, C-Type / deficiency
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism*
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Lipopolysaccharide Receptors / metabolism
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Lipopolysaccharides / toxicity
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Liver / metabolism
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Liver / pathology
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Liver Cirrhosis / chemically induced
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Liver Cirrhosis / metabolism
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Liver Cirrhosis / pathology*
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Liver Neoplasms / chemically induced
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Macrophage Colony-Stimulating Factor / genetics
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Macrophage Colony-Stimulating Factor / metabolism
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Macrophage Colony-Stimulating Factor / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / pharmacology
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Sepsis / etiology
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Signal Transduction / drug effects
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Thioacetamide / toxicity
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / metabolism*
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Up-Regulation / drug effects
Substances
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Ccl2 protein, mouse
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Chemokine CCL2
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Cytokines
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Lectins, C-Type
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Recombinant Proteins
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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dectin 1
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Thioacetamide
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Diethylnitrosamine
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Macrophage Colony-Stimulating Factor