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 - 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
SN - 2211-1247
VL - 13
SP - 1909
EP - 1921
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -
