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

2015; Cell Press; Volume: 13; Issue: 9 Linguagem: Inglês

10.1016/j.celrep.2015.10.058

2639-1856

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, E Van Heerden, Antonina Avanzi, Rocky Barilla, Constantinos P. Zambirinis, Mauricio Rendon, Donnele Daley, H. Leon Pachter, Cristina Hajdu, George Miller,

Advanced Glycation End Products research

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.