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Statin therapy and autoimmune disease: from protein prenylation to immunomodulation

Key Points

  • 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, reduce the conversion of HMG-CoA to L-mevalonate and therefore the downstream biosynthesis of cholesterol. There is increasing awareness that many of the beneficial effects of statins are mediated not through the depletion of cholesterol but through modulation of the immune system.

  • A key cholesterol-independent effect of statins is the inhibition the biosynthesis of isoprenoids that are essential for the post-translational modification and function of various important signalling proteins, including those of the small GTPase family. Many of these prenylated proteins are involved in orchestrating immune responses.

  • Statins attenuate antigen presentation to CD4+ T cells by inhibiting interferon-γ-induced MHC class II and co-stimulatory molecule expression and by interfering with antigen uptake and processing. T-cell proliferation is also impaired by statin-mediated inhibition of cytoskeletal remodelling.

  • By altering transcriptional control of T-cell differentiation statins induce a bias towards T helper 2 (TH2)-cell differentiation and away from TH1-cell differentiation.

  • Leukocyte trafficking is impaired as statins alter the expression of cell-adhesion molecules, chemokines, chemokine receptors and matrix metalloproteinases and inhibit adhesion-molecule signalling required for transvascular migration. Through their effect on cytoskeletal reorganization, statins also reduce leukocyte motility.

  • In most cases, the treatment of animal models of autoimmune disease with statins elicits an improvement in clinical outcome that can be attributed to the effects highlighted above. In the few preliminary clinical trials reported so far, there is an indication that statins confer some clinical benefit.

  • Despite several concerns, the high degree of patient tolerance and their simplicity of delivery make statins an attractive addition to currently available strategies for treating autoimmune disease.

Abstract

Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents for the treatment of autoimmune disease. Modulation of post-translational protein prenylation seems to be a key mechanism by which statins alter immune function. In this Review, the effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.

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Figure 1: The cholesterol synthesis pathway and protein prenylation.
Figure 2: The effect of statins on T-cell and antigen-presenting cell function.
Figure 3: The effect of statins on leukocyte adhesion and migration and endothelial-cell immune function.

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Acknowledgements

J.G. acknowledges support from The Wellcome Trust and Multiple Sclerosis Society (UK). L.S. acknowledges the support of the National Institutes of Heath, the National Multiple Sclerosis Society and the Phil N. Allen Trust. S.S.Z. is funded by the National Institutes of Heath, the National Multiple Sclerosis Society, The Dana Foundation and the Maisin Foundation.

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DATABASES

Medscape Drug Reference

Atorvastatin

Lovastatin

Simvastatin

OMIM

multiple sclerosis

systemic lupus erythematosus

FURTHER INFORMATION

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Lawrence Steinman's laboratory

Scott S. Zamvil's homepage

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Greenwood, J., Steinman, L. & Zamvil, S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6, 358–370 (2006). https://doi.org/10.1038/nri1839

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