Statins, inhibitors of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production

Abstract

Objective. Statins, which are used as cholesterollowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs.Methods. We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFN␣ production, and intracellular signaling.Results. Statins inhibited IFN␣ production profoundly and tumor necrosis factor ␣ production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFN␣ production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFN␣ production by PDCs from SLE patients and SLE serum-induced IFN␣ production.Conclusion. Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.Statins, inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, represent the most important cholesterol-lowering agents used to treat hypercholesterolemia. Recent clinical and experimental evidence indicates that statins have pleiotropic effects that include antiinflammatory and immunomodulatory properties, as shown by reduced rates of graft rejection in statin-treated patients after heart transplantation (1), beneficial effects in autoimmune encephalomyelitis or multiple sclerosis (2,3), decreased leukocyte recruitment and edema formation in animal models of acute inflammation (4), and delayed disease progression in the

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…This has been demonstrated with blood-derived PDC obtained from healthy donors, as well as from patients with SLE 97 . Statin treatment also inhibits TNF secretion by human PDC in response to either TLR7 (loxoribine) or TLR9 (CpGA) ligands 97 . These data have been confirmed in vivo using ssRNA Sendai virus 97 .…”

“…Inhibition of the mevalonate pathway ( i.e ., de novo cholesterol biosynthesis) by statins (simvastatin and pitavastatin) blocks TLR7- and TLR9-induced type I IFN production by human PDC ( Figure 3) 97 . This has been demonstrated with blood-derived PDC obtained from healthy donors, as well as from patients with SLE 97 .…”

“…Statin treatment also inhibits TNF secretion by human PDC in response to either TLR7 (loxoribine) or TLR9 (CpGA) ligands 97 . These data have been confirmed in vivo using ssRNA Sendai virus 97 . Inhibition of de novo cholesterol synthesis by statins in PDC interferes with the p38 MAPK pathway, Akt and nuclear translocation of IRF7 ( Figure 3) 97 .…”

The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review

“…Amuro et al [46] isolated human plasmacytoid dendritic cells, essential to the development of systemic lupus erythematosus and found that treatment with statins inhibited the production of pro-inXammatory cytokines interferon-alpha and tumor necrosis factor-alpha. In addition to chemokine downregulation [47], statins also positively modify cholesterol lipid rafts in T cells, resulting in inhibition of cellular activation and production of interleukins [48].…”

Pediatric Statin Administration: Navigating a Frontier with Limited Data

“…For example, patients with sickle cell disease can develop oxidative stress and chronic inflammation to their distal vasculature as a result of transient vaso-occlusion and subsequent [196][197][198] Decrease decline in GFR Prevent contrast induced acute kidney injury Decrease risk of stroke Fracture injuries, bone healing, & osteoporosis [199][200][201][202][203][204] Promote mesenchymal cell differentiation to osteoblasts Protect osteoblasts from apoptosis Reduce osteoclast activity and bone resorption HIV [205][206][207][208][209][210][211] Slow progression of vascular disease on ART Improve flow-mediated vasodilation Implement immunomodulation Reduce all-cause mortality Immunomodulation [212][213][214] Inhibit interferon production Decrease T cell activation Infection [215][216][217][218] Reduce risk of mortality from bacterial and viral infection Lupus [219][220][221][222] Reduce C-reactive protein Reduce circulating chemokines Improve endothelial function Polycystic ovary syndrome [223][224][225] Reduce markers of inflammation Reduce androgenic steroid concentrations Rheumatoid arthritis [226][227][228][229][230][231] Reduce risk of mortality Reduce joint pain/swelling Reduce markers of inflammation Rotator cuff injury 232,233 Stimulate migration and adhesi...…”