Suppression of Autoimmune Retinal Disease by Lovastatin Does Not Require Th2 Cytokine Induction

Abstract

Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the HMG-CoA reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage and leukocytic infiltration into the retina. Efficacy was reversed by co-administration of mevalonolactone, the downstream product of HMG-CoA reductase, but not by squalene which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 ± 0.03μM, did not result in splenocyte production of Th2 cytokines but did cause a small reduction in antigen-induced T cell proliferation and a decrease in the production of IFN-γ and IL-10. Thus, contrary to expected outcome we demonstrate that it is possible to dissociate the therapeutic effect of statins from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1 mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment failed to attenuate retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.

Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

“…Most studies relating to the immunomodulatory properties of statins in autoimmunity have studied their effects on animal models of disease with a predominant Th1-driven response (2,3). However, induction of a Th2 cytokine response by statins has not been a universal feature in rodent models of autoimmune disease (48) or in human primary PBMC from patients with multiple sclerosis, where an in vitro study observed an increase in IFN-␥ and reduction in IL-10 production (49). Th1 and Th2 cytokines both contribute to the pathogenesis of lupus disease, which is not so easily defined within the classical Th1/Th2 paradigm (50).…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…This effect was reversed with mevalonate but not with squalene, suggesting an action on one or more prenylated proteins. The cell type(s) through which lovastatin mediated this effect is unclear, but lovastatin significantly suppressed in vitro transendothelial migration of mouse lymphocytes; lymphocyte transmigration was restored with the addition of mevalonate (124).…”

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

“…This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppression of Th1-type cytokine secretion through a mechanism involving primarily their inhibitory effects on isoprenoid biosynthesis [7,12]. Conversely, atorvastatin does not appear to affect the Th1/Th2 balance either in an experimental autoimmune uveitis mouse model [13] or in autoimmune diabetes in NOD mice [14].…”