FOXE1 Contributes to the Development of Psoriasis by Regulating WNT5A

Psoriasis is a common, chronic and relapsing inflammatory skin disease characterized by hyperproliferation of keratinocytes (KCs) and infiltration of immune cells. The pathogenesis of psoriasis is complex and the exact mechanism remains partially understood. Here we showed that the forkhead box family protein, FOXE1 had increased expression in lesional skins versus non-lesional skins from psoriatic patients. FOXE1 expression was also increased in imiquimod (IMQ)-induced psoriatic mouse model as well as in M5-stimulated KCs. Using combinational approaches of knockdown and overexpression of FOXE1, we demonstrated that FOXE1 may promote the proliferation of KCs by facilitating G1/S transition and activating ERK1/2 signaling pathway. In addition, knockdown of FOXE1 reduced the production of IL-1β, IL-6 and TNF-α by KCs. RNA-sequencing profiling identified Wnt5a as a potential downstream effector of FOXE1. Knockdown of Wnt5a inhibited the proliferation of KCs, reduced the production of IL-1β, IL-6 and TNF-α by KCs and mitigated the growth-promoting effect of FOXE1 in FOXE1-overexpressed KCs. Finally, depletion of FOXE1 by lentiviral delivery of shRNAs or genetic approach ameliorated dermatitis symptoms in IMQ-induced psoriasis-like mouse models. Taken together, our results indicated that FOXE1 participates in the pathogenesis of psoriasis and can serve as a target of psoriasis treatment.