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

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 reduce the antiviral immune response; however, underlying molecular mechanisms unclear. Here, we found that simvastatin decreased polyinosinic–polycytidylic acid [poly(I:C)]-induced expression of interferon (IFN)-? and IFN-stimulated genes (ISGs) in bronchoalveolar lavage fluid (BALF) lungs mice with high-fat diet-induced hyperlipidemia. Macrophages were dominant cell type BALF poly(I:C)-treated mice. We examined effects primary lung macrophages suppressed poly(I:C)-induced IFN-? ISGs. statin-mediated inhibition gene using murine macrophage-like line, J774.1/JA-4. Simvastatin pitavastatin Moreover, they repressed phosphorylation IFN regulatory factor (IRF) 3 signal transducers activators transcription (STAT) 1, which involved Janus kinase (JAK)/STAT signaling. Mevalonate geranylgeranyl pyrophosphate (GGPP), but not cholesterol, counteracted negative effect statins on ISG IRF3 STAT1. The geranylgeranyltransferase inhibitor ISGs These results suggest hyperlipidemic these occurred through JAK/STAT signaling macrophages. Furthermore, GGPP recovered statin-suppressed