TY - JOUR
T1 - Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways
AU - Seifert, Lena
AU - Deutsch, Michael
AU - Alothman, Sara
AU - Alqunaibit, Dalia
AU - Werba, Gregor
AU - Pansari, Mridul
AU - Pergamo, Matthew
AU - Ochi, Atsuo
AU - Torres-Hernandez, Alejandro
AU - Levie, Elliot
AU - Tippens, Daniel
AU - Greco, Stephanie H.
AU - Tiwari, Shaun
AU - Ly, Nancy Ngoc Giao
AU - Eisenthal, Andrew
AU - van Heerden, Eliza
AU - Avanzi, Antonina
AU - Barilla, Rocky
AU - Zambirinis, Constantinos P.
AU - Rendon, Mauricio
AU - Daley, Donnele
AU - Pachter, H. Leon
AU - Hajdu, Cristina
AU - Miller, George
N1 - Funding Information:
This work was supported by grants from the American Liver Foundation (A.T.-H., L.S., and M.D.), the German Research Foundation (L.S.), the Schwartz Fellowship in GI Oncology (D.D.), the Society of University Surgeons (A.T.-H.) and National Institute of Health Awards DK085278 (G.M.), DK098303 (G.M.), and CA 168611 (G.M.). We thank the New York University Langone Medical Center (NYU LMC) Histopathology Core Facility, supported in part by the Cancer Center Support grant P30CA01608; the NYU LMC Flow Cytometry Core Facility, supported in part by the Cancer Center Support grant P30CA016087; the NYU LMC Microscopy Core Facility; and the NYU LMC BioRepository Center, supported in part by the Cancer Center Support Grant P30CA016087, and by grant UL1 TR000038 from the National Center for the Advancement of Translational Science (NCATS).
Publisher Copyright:
© 2015 The Authors.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.10.058
DO - 10.1016/j.celrep.2015.10.058
M3 - Article
C2 - 26655905
AN - SCOPUS:84947557486
VL - 13
SP - 1909
EP - 1921
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 9
ER -
