The non-transcriptional activity of IRF3 modulates hepatic immune cell populations in acute-on-chronic ethanol administration in mice.
J Hepatol
; 70(5): 974-984, 2019 05.
Article
en En
| MEDLINE
| ID: mdl-30710579
ABSTRACT
BACKGROUND & AIMS:
Interferon regulatory factor 3 (IRF3) is a transcription factor mediating antiviral responses, yet recent evidence indicates that IRF3 also has critical non-transcriptional functions, including activating RIG-I-like receptors-induced IRF-3-mediated pathway of apoptosis (RIPA) and restricting activity of NF-κB. Using a novel murine model expressing only non-transcriptional IRF3 activity (Irf3S1/S1), we tested the hypothesis that non-transcriptional functions of IRF3 modulate innate immune responses in the Gao-binge (acute-on-chronic) model of alcohol-related liver disease.METHODS:
IRF3 and IRF3-mediated signals were analysed in liver samples from 5 patients transplanted for alcoholic hepatitis and 5 healthy controls. C57BL/6, Irf3-/- and Irf3S1/S1 mice were exposed to Gao-binge ethanol-induced liver injury. IRF3-mediated RIPA was investigated in cultured macrophages.RESULTS:
Phospho-IRF3 and IRF3-mediated signals were elevated in livers of patients with alcoholic hepatitis. In C57BL/6 mice, Gao-binge ethanol exposure activated IRF3 signaling and resulted in hepatocellular injury. Indicators of liver injury were differentially impacted by Irf3 genotype. Irf3-/-, but not Irf3S1/S1, mice were protected from steatosis, elevated alanine/aspartate aminotransferase levels and inflammatory cytokine expression. In contrast, neutrophil accumulation and endoplasmic reticulum stress were independent of genotype. Protection from Gao-binge injury in Irf3-/- mice was associated with an increased ratio of Ly6Clow (restorative) to Ly6Chigh (inflammatory) cells compared to C57BL/6 and Irf3S1/S1 mice. Reduced ratios of Ly6Clow/Ly6Chigh in C57BL/6 and Irf3S1/S1 mice were associated with increased apoptosis in the Ly6Clow population in response to Gao-binge. Activation of primary macrophage cultures with Poly (IC) induced translocation of IRF3 to the mitochondria, where it associated with Bax and activated caspases 3 and 9, processes indicative of activation of the RIPA pathway.CONCLUSIONS:
Taken together, these data identify that the non-transcriptional function of IRF3 plays an important role in modulating the innate immune environment in response to Gao-binge ethanol exposure, via regulation of immune cell apoptosis. LAYSUMMARY:
Activation of the innate immune system contributes to inflammation in the progression of alcohol-related liver disease, as well as to the resolution of injury. Here we show that the protein IRF3 modulates the innate immune environment of the liver in a mouse model of alcoholic hepatitis. It does this by increasing the apoptotic cell death of immune cells that promote the resolution of injury.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factor 3 Regulador del Interferón
/
Hepatitis Alcohólica
/
Hígado
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Hepatol
Asunto de la revista:
GASTROENTEROLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos