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

• Published in: The FEBS journal 2021-07, Vol.288 (14), p.4249-4266
• Main Authors: Koike, Atsushi, Tsujinaka, Kaito, Fujimori, Ko
• Format: Article
• Language: English
• Subjects: Antiviral agents; Bronchus; Cholesterol; Coenzyme A; Gene expression; Geranylgeranyltransferase; High fat diet; Hyperlipidemia; Immune response; Immunosuppressive agents; Interferon; Interferon regulatory factor 3; IRF3; JAK/STAT; Janus kinase; Kinases; Lungs; macrophage; Macrophages; Mevalonic acid; Molecular modelling; Phosphorylation; Polyinosinic:polycytidylic acid; Reductases; Signaling; Simvastatin; Stat1 protein; statin; Statins; TLR; Transcription factors; Transducers
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.15712

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. Statins are cholesterol‐lowering drugs that are widely used for the treatment of dyslipidemia and cardiovascular diseases. These drugs are also known to exert anti‐inflammatory and immunomodulatory effects via hitherto poorly understood mechanisms. Here, Ko Fujimori et al. examined the effect of statins on the antiviral immune response in poly(I:C)‐treated hyperlipidemic mice and murine macrophages. They show that statins suppress the expression of antiviral interferon (IFN)‐β and IFN‐stimulated genes (ISGs) and that in macrophages, th