title: Mincle Signaling Promotes Con A Hepatitis.
abstract: Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPβ and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ-related signaling intermediates C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPβ and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Stephanie H
authors: SH
authors: Greco
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Alejandro
authors: A
authors: Torres-Hernandez
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Aleksandr
authors: A
authors: Kalabin
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Clint
authors: C
authors: Whiteman
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Rae
authors: R
authors: Rokosh
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Sushma
authors: S
authors: Ravirala
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Atsuo
authors: A
authors: Ochi
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Johana
authors: J
authors: Gutierrez
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Muhammad Atif
authors: MA
authors: Salyana
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Vishnu R
authors: VR
authors: Mani
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Savitha V
authors: SV
authors: Nagaraj
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Michael
authors: M
authors: Deutsch
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Lena
authors: L
authors: Seifert
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Donnele
authors: D
authors: Daley
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Rocky
authors: R
authors: Barilla
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Mautin
authors: M
authors: Hundeyin
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Yuriy
authors: Y
authors: Nikifrov
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Karla
authors: K
authors: Tejada
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016;
authors: Bruce E
authors: BE
authors: Gelb
authors: Immunotherapy Program, Roger Williams Medical Center, Providence, RI 02908; and.
authors: Steven C
authors: SC
authors: Katz
authors: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016; Department of Cell Biology, New York University School of Medicine, New York, NY 10016 george.miller@nyumc.org.
authors: George
authors: G
authors: Miller
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000276:immunology*; D004195:Disease Models, Animal; D006505:Hepatitis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D037181:Lectins, C-Type / Q000172:deficiency / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009573:Nitrites / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C113583:Clecsf8 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009573:Nitrites; D003208:Concanavalin A