Cell Reports
(Dec 2015)
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 Rendon,
Donnele Daley,
H. Leon Pachter,
Cristina Hajdu,
George Miller
Affiliations
Lena Seifert
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Michael Deutsch
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Sara Alothman
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Dalia Alqunaibit
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Gregor Werba
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Mridul Pansari
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Matthew Pergamo
Department of Pathology, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Atsuo Ochi
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Alejandro Torres-Hernandez
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Elliot Levie
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Daniel Tippens
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Stephanie H. Greco
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Shaun Tiwari
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Nancy Ngoc Giao Ly
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Andrew Eisenthal
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Eliza van Heerden
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Antonina Avanzi
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Rocky Barilla
Department of Pathology, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Constantinos P. Zambirinis
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Mauricio Rendon
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Donnele Daley
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
H. Leon Pachter
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Cristina Hajdu
Department of Pathology, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
George Miller
Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
DOI
https://doi.org/10.1016/j.celrep.2015.10.058
Journal volume & issue
Vol. 13,
no. 9
Abstract
Read online
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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