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.
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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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.
The authors declare no competing financial interests.
A clinical condition in which there is abnormally high circulating levels of blood cholesterol, which can be a significant contributing factor towards cardiovascular disease.
- Low-density lipoprotein (LDL) cholesterol
Cholesterol is carried in the blood by proteins in the form of lipoproteins. There are five different lipoproteins, with cardiovascular risk associated with high circulating levels of LDL cholesterol.
Prenylation (or isoprenylation) is the post-translational modification of a protein through the addition of an isoprenoid lipid; namely the 15-carbon farnesyl or 20-carbon geranylgeranyl lipid moiety derived from the cholesterol synthesis pathway.
The measure of a molecules ability to dissolve in lipid (oil) as opposed to water. Lipophilic or 'lipid-loving' molecules show a preference for dissolving in lipids.
- Outside–in signalling
The initiation of an intracellular signalling pathway through extracellular ligand engagement of a cell-surface receptor.
- Gadolinium-enhancing lesions
Damaged areas (lesions) detected by magnetic resonance imaging (MRI) that have been enhanced by the intravenous administration of a contrast agent (gadolinium) to increase the sensitivity of MRI scans.
- Expanded disability status scale (EDSS) score
A widely used neurological and functional scoring system for judging the clinical status of people with multiple sclerosis.
Severe muscle toxicity resulting in the breakdown of muscle fibres. A potential side-effect of statins, either in monotherapy or in combination therapy.
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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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