Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways

Cell Rep. 2015 Dec 1;13(9):1909-1921. doi: 10.1016/j.celrep.2015.10.058. Epub 2015 Nov 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / drug effects
  • Cells, Cultured
  • Chemokine CCL2 / blood
  • Cytokines / metabolism
  • Diethylnitrosamine / toxicity
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Inflammation
  • Lectins, C-Type / deficiency
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / toxicity
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / pharmacology
  • Sepsis / etiology
  • Signal Transduction / drug effects
  • Thioacetamide / toxicity
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / metabolism*
  • Up-Regulation / drug effects

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Cytokines
  • Lectins, C-Type
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Recombinant Proteins
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • dectin 1
  • Thioacetamide
  • Diethylnitrosamine
  • Macrophage Colony-Stimulating Factor