Abstract
Purpose To evaluate the regulating effect of Notch-Hes1 signaling on IL-17A+γδ+T cell expression and IL-17A secretion in mouse psoriasis-like skin inflammation. Materials and Methods Experimental mice were randomly divided into control group, model group (5% imiquimod- (IMQ-) treated mice), and intervention group (IMQ and γ-secretase inhibitor DAPT cotreated mice). The severity of psoriasis-like skin inflammation was evaluated by target lesion score based on the clinical psoriasis area and severity index (PASI). Flow cytometry detected IL-17A+γδ+T cell percentage. Quantitative real-time RT-PCR detected Hes1 mRNA expression. Enzyme-linked immunosorbent assay and western blot measured IL-17A serum concentration and protein expression. Additionally, splenic single cells from model mice were treated by DAPT to further evaluate the inhibitory effect of blocking Notch-Hes1 signaling on IL-17A+γδ+T cell differentiation and IL-17A secretion. Results The spleen index, IL-17A+γδ+T cell percentage, Hes1 mRNA expression, IL-17A serum concentration, and protein expression were all significantly higher in model mice than control mice, while dramatically reduced in intervention mice by DAPT treatment, which also obviously alleviated the target lesion score, epidermal hyperplasia, and dermal inflammatory cell infiltration of intervention mice. In vitro study demonstrated that DAPT treatment could result in dose-dependent decrease of IL-17A+γδ+T cell percentage and IL-17A secretion in splenic single cells of model mice.
Highlights
Psoriasis is an immune-mediated chronic, recurrent, and inflammatory skin disorder, which is characterized by epidermal proliferation and massive infiltration of immune cells, producing lots of cytokines, chemokines, and inflammatory molecules [1]
The control mice did not present any sign of skin inflammation during consecutive 6 days
Growing evidence indicated that psoriasis is strongly associated with IL-17A, and clinically, the monoclonal antibodies to IL-17A or its receptor IL-17R showed a dramatic effect against psoriasis [2,3,4, 6,7,8,9,10,11,12]
Summary
Psoriasis is an immune-mediated chronic, recurrent, and inflammatory skin disorder, which is characterized by epidermal proliferation and massive infiltration of immune cells, producing lots of cytokines, chemokines, and inflammatory molecules [1]. The pathogenesis of psoriasis has not been fully understood, growing evidence indicated that the cytokine interleukin- (IL-) 17 plays key roles in the development of psoriasis [2,3,4]. In the animal model of mouse psoriasis-like skin inflammation, the critical roles of IL-17 have been confirmed [5]. Previous studies suggested that IL-17A was mainly produced by Th17 cells in psoriatic lesions [13, 14]. ΓδT cells have been recently reported to be a major IL-17A producer in human psoriatic lesion and mouse psoriasis-like skin inflammation [18]
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