Abstract
Alopecia areata (AA) is a T-cell-mediated disorder characterized by autoimmune attack on the hair follicle and consequent hair loss. At present, existing therapies are associated with troubling side effects, low response, or prohibitive expense. Here, we demonstrate that 3 months’ daily topical simvastatin (SIM) induces hair re-growth in C3H mice with AA. SIM decreased inflammatory markers in lesional skin, as well as (p)Stat1 and NKG2D levels in skin-draining lymph node cells (LNCs). Complete hair re-growth corresponded to lower serum cholesterol and triglycerides, compared to partial and non-responders. SIM was also found to decrease population growth and viability in CD8+ CTLL-2 cells, as well as Ki67 expression in CD4+ and CD8+ LNCs. SIM’s inhibitory effect on CTLL-2 cells was reversed by the addition of isoprenoid metabolites. Increased IL-2 concentration served to partially restore SIM-inhibited CTLL-2 proliferation, and the IL-2-inducible Stat5 activation was found to decrease steadily with SIM treatment of CTLL-2 cells. SIM also significantly inhibited IFN-γ production by primary CD8+ T cells. Overall, the results herein strongly support simvastatin’s potential as a therapeutic agent for AA and indicate that SIM-induced remission of AA is due to inhibitory effects on CD8+ T cells and on the signaling of crucial cytokines. These effects seem to be partially mediated by the inhibition of protein isoprenylation.