Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Pages (from-to) | 1909-1921 |
Number of pages | 13 |
Journal | Cell reports |
Volume | 13 |
Issue number | 9 |
Publication status | Published - 1 Dec 2015 |
Peer-reviewed | Yes |
Externally published | Yes |
External IDs
PubMedCentral | PMC4681001 |
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Scopus | 84947557486 |
Keywords
Sustainable Development Goals
Keywords
- Animals, Cell Transformation, Neoplastic/drug effects, Cells, Cultured, Chemokine CCL2/blood, Cytokines/metabolism, Diethylnitrosamine/toxicity, Hepatocytes/cytology, Humans, Inflammation, Lectins, C-Type/deficiency, Lipopolysaccharide Receptors/metabolism, Lipopolysaccharides/toxicity, Liver/metabolism, Liver Cirrhosis/chemically induced, Liver Neoplasms/chemically induced, Macrophage Colony-Stimulating Factor/genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Recombinant Proteins/biosynthesis, Sepsis/etiology, Signal Transduction/drug effects, Thioacetamide/toxicity, Toll-Like Receptor 4/antagonists & inhibitors, Up-Regulation/drug effects