3C3 alleviates atopic dermatitis-like phenotypes through cyclophilin A and B-mediated inhibition of calcineurin-NFAT pathway.

Atopic dermatitis (AD) disrupts a patients' quality of life and is associated with other atopic disorders, such as food allergy, allergic rhinitis, and asthma. Although topical medications are widely used, they have undesirable side effects, suggesting the need for treatments with improved efficacy and safety. In this study, we identified 3C3 as a candidate compound for AD treatment using in vitro TNFα-treated HaCaT keratinocytes and a DNFB-induced AD mouse model. 3C3 treatment alleviated AD-like phenotypes and suppressed the gene activation of pro-inflammatory cytokine. We further found that 3C3 binds to cyclophilin A (CypA) and cyclophilin B (CypB), inhibiting the phosphatase activity of calcineurin. 3C3 treatment suppressed the nuclear translocalization and occupancy of NFAT2 and NFAT4 at gene promoters of IL-6, IL-13, IL-31, and IL-33 in PAR2 activated HaCaT keratinocytes. This resulted in suppression of PAR2 agonist-induced gene activation of IL-6, IL-13, IL-31, and IL-33. In addition, unlike glucocorticoids, 3C3 did not induce skin atrophy through upregulation of REDD1 and reduction of mTOR signaling. Our study suggests that 3C3 may help alleviate skin inflammatory diseases including AD, through a mechanism similar to that of cyclosporine A, whose use is limited due to side effects such as nephrotoxicity.