Statin therapy and autoimmune disease: from protein prenylation to immunomodulation

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.

Figure 1

The cholesterol synthesis pathway and protein prenylation. Statins inhibit the conversion of HMGCoA to L-mevalonate through competitive inhibition of the rate limiting enzyme HMGCoA reductase. This inhibition results in a decrease in the downstream biosynthesis of cholesterol and other intermediate metabolites including the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoid pyrophosphates serve as essential adjuncts in the posttranslational modification of numerous key proteins that act as molecular switches including the small GTPases Ras, Rac and Rho. The posttranslational modification enables these signaling proteins to associate with membranes which are requisite for most of their biological function.

Figure 2

The effect of statins on T-cell/antigen presenting cell function. Statins inhibit cytokine-inducible expression of MHC class II molecules and co-stimulatory molecules on antigen-presenting cells (APCs) and prevent antigen presentation to CD4⁺ T cells. T-cell proliferation is abrogated through modulation of GTPase-linked regulation of cell cycle progression and proliferation. In addition, the effect of statins on cytoskeletal organization will interfere with formation of the immune synapse. Statins also alter the T-cell profile by inhibiting the secretion of pro-inflammatory cytokines through phosphorylation of STAT4 (signal transducer and activator of transcription 4) and induction of the transcription factor T-bet which are required for T_H1 differentiation. Conversely, statins may also enhance the secretion of anti-inflammatory T_H2 cytokines via the activation of both STAT6 and GATA3 (GATA-binding protein 3), which are involved in T_H2-cell differentiation.

Figure 3

The effect of statins on leukocyte adhesion and migration and endothelial cell immune function. Cell-adhesion molecule expression on leukocytes and endothelia are attenuated by statins, resulting in reduced adhesion and transvascular migration. In addition, statins inhibit chemokine and matrix metalloproteinase (MMP) secretion, which will further interfere with leukocyte migration. In the endothelium, adhesion molecule signaling necessary for leukocyte migration is blocked through the modulation of Rho and other small GTPases. This may also result in stabilization of the endothelial cell-cell junction. The effect of statins on the cytoskeleton alters leukocyte motility and directional migration in response to chemotactic gradients.