Sphingosine 1-phosphate (S1P) is a bioactive phospholipid that signals through five cell surface receptors (S1P1-5). Despite the role of S1P receptors in lymphocyte trafficking and epidermal keratinocyte proliferation and differentiation, their role in hair follicle (HF) physiology remains obscure. We hypothesized that S1P receptor activation may be involved in alopecia areata (AA), a T cell-mediated hair loss disorder characterized by immune privilege (IP) collapse in the hair bulb. RNAseq revelated S1P1,3,5 are expressed in human scalp HFs. By in situ hybridization and immunostaining, we confirmed the expression of S1P1,5 in HF epithelium and mesenchyme. Ex vivo treatment of human scalp HFs with the selective S1P1,4,5 modulator etrasimod led to enrichment of keratinization-associated genes, tendential prolongation of anagen, and preservation of IP. The anagen-prolonging effect of etrasimod was reproduced in human scalp skin organ culture, even under pro-inflammatory conditions induced with IFNg, the key pathological cytokine in AA. Etrasimod prevented IFNg-dependent IP collapse and inhibited the increase of perifollicular CD8+ lymphocytes. Supporting the potential role in AA, S1P1,5 were expressed in immune cells within the infiltrate around the bulb, and the intrafollicular epithelial expression of S1P1,5 was increased in the HFs of patients compared to healthy controls. Taken together, these results suggest that S1P receptor signaling is involved in the regulation of hair growth and preservation of IP in HF, and may also be involved in IP collapse and T cell recruitment in AA. These preliminary findings invite the investigation of targeting S1P receptors for AA management.

ESDR020 - Sphingosine 1-phosphate receptor signalling promotes hair growth and inhibits perifollicular T-cell expansion and immune privilege collapse ex vivo

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING