title: Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways.
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.
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Lena
authors.initials: L
authors.lastname: Seifert
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Michael
authors.initials: M
authors.lastname: Deutsch
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Sara
authors.initials: S
authors.lastname: Alothman
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Dalia
authors.initials: D
authors.lastname: Alqunaibit
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Gregor
authors.initials: G
authors.lastname: Werba
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Mridul
authors.initials: M
authors.lastname: Pansari
authors.affiliation: S. Arthur Localio Laboratory, Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pergamo
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Torres-Hernandez
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Elliot
authors.initials: E
authors.lastname: Levie
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tippens
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Greco
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Shaun
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Nancy Ngoc Giao
authors.initials: NNG
authors.lastname: Ly
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Andrew
authors.initials: A
authors.lastname: Eisenthal
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Eliza
authors.initials: E
authors.lastname: van Heerden
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Antonina
authors.initials: A
authors.lastname: Avanzi
authors.affiliation: S. Arthur Localio Laboratory, Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Rocky
authors.initials: R
authors.lastname: Barilla
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Zambirinis
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rendon
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Donnele
authors.initials: D
authors.lastname: Daley
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: H Leon
authors.initials: HL
authors.lastname: Pachter
authors.affiliation: S. Arthur Localio Laboratory, Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hajdu
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016.|S. Arthur Localio Laboratory, Department of Cell Biology New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology; D018805:Sepsis / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects; D013853:Thioacetamide / Q000633:toxicity; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000099181:Dectin-1
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D004052:Diethylnitrosamine; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016173:Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D013853:Thioacetamide; D051197:Toll-Like Receptor 4; D000099181:Dectin-1; C491768:Ccl2 protein, mouse; C493487:Tlr4 protein, mouse
keywords: C-type lectin receptors; hepatocellular cancer; liver fibrosis