Effective Inhibition Of Th17 Pathway In 2d And 3d Models Of Psoriasis By Celastrol Enriched Plant Cell Culture Extract (Cee)

Psoriasis is an immune-mediated inflammatory disease where Th17 pathway is mainly involved. Systemic interventions with biologics to block specifically Th17 pathway are now effective to treat severe psoriasis. However, for efficient topical treatment, small molecule is more suitable than antibody to penetrate and target epidermal keratinocytes, the key players in psoriasis. Celastrol, a well-described triterpene, is present in low amount in Tripterygium wilfordii roots. By plant cell culture we were able to boost Celastrol production in bioreactors. Here, we evaluated immune modulator effect of Celastrol enriched extract (CEE) in Th17 psoriasis induced models in vitro and ex vivo in view of its dermatological usage. 2D models (i) human CD4+ T lymphocytes and (ii) NHEK or (iii) 3D models (μ-epidermis and reconstituted human epidermis models) were stimulated by antiCD3/CD28 (i) or by cytokines cocktail (ii and iii) in the presence of CEE. Psoriasis biomarkers were assessed either by ELISA (hCD4+ and RHE), by RT-qPCR (NHEK) or by IHC and ELISA (μ-epidermis). In 2D stimulated models, CEE dose dependently inhibited expression of induced Th17 cytokines (i and ii). In 3D models, IL8 expression was significantly reduced (RHE) and native phenotype was restored (μ-epidermis model) by CEE. These findings showed clearly that CEE inhibited both 2D and 3D models: Th17 cytokines, key inflammatory parameters and psoriasis associated biomarkers involved in the physiopathology of this cutaneous disease. Therefore, skin homeostasis could be restored by these modulator effects. Moreover, this high added value CEE was obtained by an ecofriendly bioprocess in contrast to traditional roots obtained extracts. This is the first time, a well-defined immune-modulator CEE is proposed for adjuvant care in the prophylaxis of Psoriasis.