1367 The protective role of miR-486 for alopecia areata

      The activities of many genes implicated in the control of skin homeostasis are regulated by miRNAs. However, how miRNAs are involved in pathogenesis of alopecia areata (AA) are largely unknown. The miRNA profiling performed in AA affected skin of female C3H/HeJ mice identified miRNAs that exhibited significant changes in their expression. Microarray validation confirmed dramatic decrease in the expression of miR-486 in mouse alopecic skin, in contrast to the prominent miR-486 expression in the follicular (HF) epithelium of healthy anagen skin. Similar miR-486 expression pattern was seen in the human skin. Intradermal delivery of miR-486 mimic into C3H/HeJ mouse back skin affected by AA prevented pre-mature entrance of the HFs into catagen. This treatment resulted in the reduced expression of MHCI, and a reduction in the numbers of CD4+ and CD8+ lymphocytes in the peri- and intra-follicular skin compartments. Subcutaneous administration of miR-486 inhibitor into anagen skin of C3H/HeJ mice delayed anagen progression associated with an appearance of a high number of intrafollicular CD8+ and NKG2D+ cells. In human HFs ex vivo, inhibition of miR-486 resulted in pre-mature anagen-catagen development associated with the decreased expression of HLA and TAP2 and upregulation in ICAM1 and CADM1. miR-486 expression was negatively regulated by INF-gamma in an ex vivo model of immune privilege collapse in human HFs and in the follicular keratinocytes in vitro. Overexpression of miR-486 in the primary keratinocytes caused downregulation of the expression of the components of MHC class, Interferon and several Interleukins signalling pathways. Taken together, these data suggest that miR-486 could play a protective role in the pathogenesis of AA by preventing the collapse of HF immune privilege.