Statins attenuate antiviral IFN-β and ISG expression via inhibition of IRF3 and JAK/STAT signaling in poly(I:C)-treated hyperlipidemic mice and macrophages

FEBS J. 2021 Jul;288(14):4249-4266. doi: 10.1111/febs.15712. Epub 2021 Feb 4.

Abstract

Viral infection is a significant burden to health care worldwide. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, are widely used as cholesterol-lowering drugs. Recently, long-term statin therapy was shown to reduce the antiviral immune response; however, the underlying molecular mechanisms are unclear. Here, we found that simvastatin decreased polyinosinic-polycytidylic acid [poly(I:C)]-induced expression of antiviral interferon (IFN)-β and IFN-stimulated genes (ISGs) in the bronchoalveolar lavage fluid (BALF) and lungs of mice with high-fat diet-induced hyperlipidemia. Macrophages were the dominant cell type in the BALF of poly(I:C)-treated mice. We examined the effects of simvastatin in primary lung macrophages and found that simvastatin suppressed poly(I:C)-induced expression of IFN-β and ISGs. We examined the molecular mechanisms of statin-mediated inhibition of antiviral gene expression using murine macrophage-like cell line, J774.1/JA-4. Simvastatin and pitavastatin decreased poly(I:C)-induced expression of IFN-β and ISGs. Moreover, they repressed poly(I:C)-induced phosphorylation of IFN regulatory factor (IRF) 3 and signal transducers and activators of transcription (STAT) 1, which is involved in Janus kinase (JAK)/STAT signaling. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, counteracted the negative effect of statins on IFN-β and ISG expression and phosphorylation of IRF3 and STAT1. The geranylgeranyltransferase inhibitor suppressed poly(I:C)-induced expression of IFN-β and ISGs and phosphorylation of IRF3 and STAT1. These results suggest that statins suppressed the expression of IFN-β and ISGs in poly(I:C)-treated hyperlipidemic mice and murine macrophages and that these effects occurred through the inhibition of IRF3 and JAK/STAT signaling in macrophages. Furthermore, GGPP recovered the statin-suppressed IRF3 and JAK/STAT signaling in poly(I:C)-treated macrophages.

Keywords: IRF3; JAK/STAT; TLR; macrophage; statin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation / drug effects*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hyperlipidemias / chemically induced
  • Hyperlipidemias / drug therapy*
  • Hyperlipidemias / metabolism
  • Hyperlipidemias / pathology
  • Interferon Inducers / toxicity
  • Interferon Regulatory Factor-3 / antagonists & inhibitors
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Poly I-C / toxicity*
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Interferon Inducers
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factors
  • Irf3 protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interferon-beta
  • Janus Kinases
  • Poly I-C