The Non-transcriptional Function of IRF3 Dynamically Regulates Immune Cell Populations in Acute on Chronic Ethanol in Mice

Autores/as

  • Laura E. Nagy Department of Inflammation and Immunity, Cleveland Clinic, Cleveland OH 44195 USA
  • Carlos Garcia Sanz Department of Inflammation and Immunity, Cleveland Clinic, Cleveland OH 44195 USA
  • Kyle Poulsen Department of Inflammation and Immunity, Cleveland Clinic, Cleveland OH 44195 USA
  • Megan R McMullen Department of Inflammation and Immunity, Cleveland Clinic, Cleveland OH 44195 USA
  • Saurabh Chattopadhahay Department of Inflammation and Immunity, Cleveland Clinic, Cleveland OH 44195 USA
  • Ganes Sen Department of Inflammation and Immunity, Cleveland Clinic, Cleveland OH 44195 USA

Palabras clave:

etanol, IRF3, innate immune responses, Gao-binge model, alcohol-related liver disease.

Resumen

Introduction: Interferon regulatory factor 3 (IRF3) is a transcription factor mediating anti-viral 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 NFκB.  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.

Objective:  To prove that non-transcriptional functions of IRF3 modulate innate immune responses in the Gao-binge (acute on chronic) model of alcohol-related liver disease.

Material and Methods: C57BL/6, Irf3-/- and Irf3S1/S1 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 Irf3genotype.  Irf3-/-, but not Irf3S1/S1, mice were protected from steatosis, ALT/AST and inflammatory cytokine expression.  In contrast, neutrophil accumulation and ER 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 an increased apoptosis in the Ly6Clow population in response to Gao-binge.  Activation of primary cultures of macrophages with Poly (I:C) induced translocation of IRF3 to mitochondria, association with Bax and activation of Caspases 3 and 9, processes indicative of activation of the RIPA pathway.

Conclusions: Taken together, these data identify important contributions of the non-transcriptional function of IRF3 in modulating the innate immune environment in response to Gao-binge ethanol exposure via regulation of immune cell apoptosis.   

 

Keywords: etanol, IRF3, innate immune responses, Gao-binge model, alcohol-related liver disease.

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Publicado

2020-01-28

Cómo citar

1.
E. Nagy L, Garcia Sanz C, Poulsen K, R McMullen M, Chattopadhahay S, Sen G. The Non-transcriptional Function of IRF3 Dynamically Regulates Immune Cell Populations in Acute on Chronic Ethanol in Mice. Rev Cubana Inv Bioméd [Internet]. 28 de enero de 2020 [citado 30 de julio de 2025];38(5). Disponible en: https://revibiomedica.sld.cu/index.php/ibi/article/view/490

Número

Vol. 38 (2019): Suplemento Especial: II PanAmerican Congress of Physiological Sciences

Sección

COMUNICACIÓN BREVE

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