Mincle Signaling Promotes Con A Hepatitis
Autor: | Rocky Barilla, Rae S. Rokosh, Sushma Ravirala, Michael Deutsch, Muhammad Atif Salyana, Bruce E. Gelb, Johana Gutierrez, Stephanie H. Greco, George Miller, Donnele Daley, Clint Whiteman, Aleksandr Kalabin, Alejandro Torres-Hernandez, Vishnu R. Mani, Yuriy Nikifrov, Savitha Nagaraj, Mautin Hundeyin, Karla Tejada, Atsuo Ochi, Lena Seifert, Steven C. Katz |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Adoptive cell transfer Immunology Inflammation Biology Article Hepatitis Mice 03 medical and health sciences Liver disease 0302 clinical medicine Immune system Concanavalin A medicine Animals Humans Immunology and Allergy Lectins C-Type Receptor Nitrites Mice Knockout Liver injury Mice Inbred BALB C Innate immune system Membrane Proteins medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Leukocytes Mononuclear medicine.symptom Signal Transduction 030215 immunology |
Zdroj: | The Journal of Immunology. 197:2816-2827 |
ISSN: | 1550-6606 0022-1767 |
Popis: | 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. |
Databáze: | OpenAIRE |
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