Immune modulatory effects of statins

Abstract

Despite major advances in recent years, immunosuppressive regimens for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and graft-versus-host disease still have major adverse effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate-limiting enzyme of the l-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It was shown that blocking the l-mevalonate pathway reduces inflammation through effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates, which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore, l-mevalonate pathway downstream products play critical roles in the different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases.

Keywords: T helper type 2; inflammation; tolerance; transplantation.

Figure 1

Simplified sketch showing the mode of action of statins as immunosuppressive strategy. Statins inhibit the rate‐limiting enzyme of the mevalonate pathway leading to reduced levels of its downstream products. The pyrophosphate downstream products are critical for geranylgeranylation or farnesylation of GTPases that mediate multiple steps in the immune response such as cell migration, activation, signalling and cytokine production.