Multiple sclerosis or multiple possibilities

Abstract

Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase competitive inhibitors, that lower blood cholesterol, but also exert potent anti-inflammatory effects. The xenobiotic receptor, aryl hydrocarbon receptor (AhR), plays crucial role in the control of inflammatory responses. Evidences suggest that selected statins promote the transcription of the main AhR target gene, cytochrome P450 family 1 (Cyp1a1). Macrophages are essential components of innate and adaptive immunity, characterized by AhR expression and activity. Based on these evidences, we investigated potential AhR-mediated immune regulatory properties of statins in Bone Marrow Derived Macrophages (BMDM). We found that BMDM activation with the pro-inflammatory cytokine TNFa induced the inflammatory marker, inducible nitric oxide synthase (iNOS), which was completely prevented in BMDMs treated with TNFa in combination with specific statins, namely, atorvastatin and rosuvastatin. We confirmed high AhR expression in BMDM that was increased upon treatment with TNFa. We investigated the ability of different statins to activate AhR using a luciferase reporter assay cell lines and in BMDCs. We found that selected statins, such as atorvastatin and rosuvastatin, activated AhR in a dose dependent manner, an activation prevented in cells expressing selected AhR mutants. Notably, AhR deficient BMDMs, expressed undetectable levels of the main statin target protein HMG-CoA, which was instead highly expressed in wild type BMDMs. These data demonstrate that natural or synthetic statins can play regulatory roles in macrophages. Moreover, our results suggest a potential involvement of AhR in statin-mediated anti-inflammatory effects in macrophages.