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

Lena Seifert, Michael Deutsch, Sara Alothman, Dalia Alqunaibit, Gregor Werba, Mridul Pansari, Matthew Pergamo, Atsuo Ochi, Alejandro Torres-Hernandez, Elliot Levie, Daniel Tippens, Stephanie H. Greco, Shaun Tiwari, Nancy Ngoc Giao Ly, Andrew Eisenthal, Eliza van Heerden, Antonina Avanzi, Rocky Barilla, Constantinos P. Zambirinis, Mauricio RendonDonnele Daley, H. Leon Pachter, Cristina Hajdu, George Miller

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32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1909-1921
Number of pages13
JournalCell Reports
Volume13
Issue number9
DOIs
StatePublished - Dec 1 2015

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Seifert, L., Deutsch, M., Alothman, S., Alqunaibit, D., Werba, G., Pansari, M., Pergamo, M., Ochi, A., Torres-Hernandez, A., Levie, E., Tippens, D., Greco, S. H., Tiwari, S., Ly, N. N. G., Eisenthal, A., van Heerden, E., Avanzi, A., Barilla, R., Zambirinis, C. P., ... Miller, G. (2015). Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways. Cell Reports, 13(9), 1909-1921. https://doi.org/10.1016/j.celrep.2015.10.058