098 Simvastatin decreases AA-associated inflammation through effects on isoprenoid metabolites

Abstract

Alopecia areata (AA) is a T-cell-mediated disorder in which lymphocytic infiltrate attacks and damages the hair follicle during the anagen phase of growth, leading to varying patterns of hair loss. At present, there is no treatment approved by the FDA for AA, and those treatments currently in use are associated with worrying side effects, prohibitive expense, or low rates of response. Previously, we have demonstrated the effectiveness of the lipid-lowering treatments simvastatin and ezetimibe in restoring T regulatory cell levels and hair growth in a mouse model of AA. Here, we aim to elucidate the mechanisms by which simvastatin exerts its effects on the autoimmune condition. Hair re-growth in the mouse model was associated with reduction of inflammatory markers in the skin, as well as reduced activation of STAT1 and reduced expression of NKG2D in skin-draining lymph nodes. These changes corresponded to a significant decrease in serum cholesterol and triglycerides in mice who responded with complete hair re-growth. Simvastatin was similarly able to decrease in vitro proliferation of both the IL-2-dependent cytotoxic T cell line CTLL-2 and primary mouse CD4+ and CD8+ T lymphocytes. This effect was shown to be at least partially mediated through the statin’s effects on isoprenoid metabolite production, as the addition of exogenous farnesyl pyrophosphate and geranyl geranyl pyrophosphate restored the proliferative ability of statin-treated CTLL-2 cells. Taken together with previous findings, these results indicate an immediate effect of simvastatin on the lymphocytic subpopulations responsible for hair follicle damage in AA through disruption of isoprenylation.