RIPK1 downregulation in keratinocyte enhances TRAIL signaling in psoriasis

Publication date: Available online 10 April 2018
Source:Journal of Dermatological Science
Author(s): Nao Saito, Masaru Honma, Takashi Shibuya, Shin Iinuma, Satomi Igawa, Mari Kishibe, Akemi Ishida-Yamamoto
BackgroundPsoriasis, a common inflammatory skin disorder characterized by scaly erythema and plaques, is induced by dysregulation of dendritic cell- and T cell-mediated immune reaction. Receptor-interacting protein kinase 1 (RIPK1) regulates inflammatory signaling in response to stimuli such as TNF-α, TRAIL, and TLRs, resulting in apoptosis, necroptosis and NF-κB activation. However, the physiological relevance in human epidermis remains elusive.ObjectiveIn this study, we examined whether RIPK1 is involved in the pathogenesis of psoriasis vulgaris.MethodsSkin samples of eight patients with psoriasis vulgaris were investigated by western blotting and immunohistochemistry. The functions of RIPK1 in keratinocytes were examined by RT-PCR and ELISA in vitro. TRAIL-neutralization-experiment was employed in an imiquimod-induced murine psoriasis model.ResultsIn lesional psoriatic epidermis, RIPK1-expression was decreased compared with that in normal epidermis. Cytokines involved in the pathomechanism of psoriasis, such as IL-1β, IL-17A, IL-22 and TRAIL, reduced RIPK1-expression in normal human epidermal keratinocytes (HEK) in vitro. In addition, RIPK1-knockdown enhanced TRAIL-mediated expression of psoriasis-relating cytokines, such as IL-1β, IL-6, IL-8, TNF-α, in HEK. Numerous TRAIL-positive cells were detected in the dermis of lesional psoriatic skin, and TRAIL receptors were expressed in psoriatic epidermis and HEK in conventional cultures. Moreover, TRAIL-neutralization in an imiquimod-induced murine psoriasis model remarkably improved skin phenotypes, such as ear thickness, and TNF-α expression in lesional skin.ConclusionsThese results lead us to conclude that RIPK1-downregulation in keratinocytes increases their susceptibility to TRAIL stimulation, and plays a role in the pathogenesis of psoriasis vulgaris.



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