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

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

Author information

1
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
2
S. Arthur Localio Laboratory, Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
3
S. Arthur Localio Laboratory, Department of Cell Biology New York University School of Medicine, 550 First Avenue, New York, NY 10016.
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Contributed equally

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

PMID:
26655905
PMCID:
PMC4681001
DOI:
10.1016/j.celrep.2015.10.058
[Indexed for MEDLINE]
Free PMC Article

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