TY - JOUR
T1 - Nontranscriptional Activity of Interferon Regulatory Factor 3 Protects Mice From High-Fat Diet-Induced Liver Injury
AU - Sanz-Garcia, Carlos
AU - McMullen, Megan R.
AU - Chattopadhyay, Saurabh
AU - Roychowdhury, Sanjoy
AU - Sen, Ganes
AU - Nagy, Laura E.
N1 - Publisher Copyright:
© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Interferon regulatory factor 3 (IRF3) has both transcriptional and nontranscriptional functions. Transcriptional activity is dependent on serine phosphorylation of IRF3, while transcription-independent IRF3-mediated apoptosis requires ubiquitination. IRF3 also binds to inhibitor of nuclear factor kappa B kinase (IKKβ) in the cytosol, restricting nuclear translocation of p65. IRF3-deficient mice are highly sensitive to high-fat diet (HFD)-induced liver injury; however, it is not known if transcriptional and/or nontranscriptional activity of IRF3 confers protection. Using a mouse model only expressing nontranscriptional functions of IRF3 (Irf3S1/S1), we tested the hypothesis that nontranscriptional activity of IRF3 protects mice from HFD-induced liver injury. C57BL/6, Irf3−/−, and Irf3S1/S1 mice were fed an HFD for 12 weeks. In C57BL/6 mice, the HFD increased expression of interferon (IFN)-dependent genes, despite a decrease in IRF3 protein in the liver. The HFD had no impact on IFN-dependent gene expression Irf3−/− or Irf3S1/S1 mice, both lacking IRF3 transcriptional activity. Liver injury, apoptosis, and fibrosis were exacerbated in Irf3−/− compared to C57BL/6 mice following the HFD; this increase was ameliorated in Irf3S1/S1 mice. Similarly, expression of inflammatory cytokines as well as numbers of neutrophils and infiltrating monocytes was increased in Irf3−/− mice compared to C57BL/6 and Irf3S1/S1 mice. While the HFD increased the ubiquitination of IRF3, a response associated with IRF3-mediated apoptosis, in Irf3S1/S1 mice, protection from liver injury was not due to differences in apoptosis of hepatocytes or immune cells. Instead, protection from HFD-induced liver injury in Irf3S1/S1 mice was primarily associated with retardation of nuclear translocation of p65 and decreased expression of nuclear factor kappa B (NFκB)-dependent inflammatory cytokines. Conclusion: Taken together, these data identify important contributions of the nontranscriptional function of IRF3, likely by reducing NFκB signaling, in dampening the hepatic inflammatory environment in response to an HFD.
AB - Interferon regulatory factor 3 (IRF3) has both transcriptional and nontranscriptional functions. Transcriptional activity is dependent on serine phosphorylation of IRF3, while transcription-independent IRF3-mediated apoptosis requires ubiquitination. IRF3 also binds to inhibitor of nuclear factor kappa B kinase (IKKβ) in the cytosol, restricting nuclear translocation of p65. IRF3-deficient mice are highly sensitive to high-fat diet (HFD)-induced liver injury; however, it is not known if transcriptional and/or nontranscriptional activity of IRF3 confers protection. Using a mouse model only expressing nontranscriptional functions of IRF3 (Irf3S1/S1), we tested the hypothesis that nontranscriptional activity of IRF3 protects mice from HFD-induced liver injury. C57BL/6, Irf3−/−, and Irf3S1/S1 mice were fed an HFD for 12 weeks. In C57BL/6 mice, the HFD increased expression of interferon (IFN)-dependent genes, despite a decrease in IRF3 protein in the liver. The HFD had no impact on IFN-dependent gene expression Irf3−/− or Irf3S1/S1 mice, both lacking IRF3 transcriptional activity. Liver injury, apoptosis, and fibrosis were exacerbated in Irf3−/− compared to C57BL/6 mice following the HFD; this increase was ameliorated in Irf3S1/S1 mice. Similarly, expression of inflammatory cytokines as well as numbers of neutrophils and infiltrating monocytes was increased in Irf3−/− mice compared to C57BL/6 and Irf3S1/S1 mice. While the HFD increased the ubiquitination of IRF3, a response associated with IRF3-mediated apoptosis, in Irf3S1/S1 mice, protection from liver injury was not due to differences in apoptosis of hepatocytes or immune cells. Instead, protection from HFD-induced liver injury in Irf3S1/S1 mice was primarily associated with retardation of nuclear translocation of p65 and decreased expression of nuclear factor kappa B (NFκB)-dependent inflammatory cytokines. Conclusion: Taken together, these data identify important contributions of the nontranscriptional function of IRF3, likely by reducing NFκB signaling, in dampening the hepatic inflammatory environment in response to an HFD.
UR - http://www.scopus.com/inward/record.url?scp=85083346795&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083346795&partnerID=8YFLogxK
U2 - 10.1002/hep4.1441
DO - 10.1002/hep4.1441
M3 - Article
AN - SCOPUS:85083346795
SN - 2471-254X
VL - 3
SP - 1626
EP - 1641
JO - Hepatology Communications
JF - Hepatology Communications
IS - 12
ER -