Abstract
BackgroundTh17 cells and its effective cytokine IL-17A play an important role in the pathogenesis of abnormal immune responses in psoriasis. Notch1 signaling has been implicated in Th17 cell differentiation and function. In this study, our aim was to evaluate the possible inhibitory effect of Notch1 signaling inhibitor, γ-secretase inhibitor DAPT, on psoriatic Th17 cell differentiation and function in a mouse model of psoriasis-like skin inflammation.MethodsMouse psoriasis-like skin inflammation model was established by topical 5% imiquimod (IMQ) application, and experimental mice were divided into control group, IMQ-treated group and IM + DAPT-treated group. DAPT and the equivalent amount of Dimethyl sulfoxide was intraperitoneally injected in IMQ + DAPT-treated group and the other two experimental groups respectively. Skin tissues of the three experimental groups were acquired and stained with haematoxylin and eosin (HE). Splenic single-cells and serum were collected to detect the percentage of Th17 cells, the mRNA expression levels of Notch1 and its target gene Hes-1, Th17-specific transcription factor RORγt and its effective cytokines IL-17A, as well as IL-17A serum concentration. In addition, splenic CD4+ T cells from IMQ-treated mice were isolated and treated by DAPT to further measure the inhibitory effect of DAPT on the Th17 cell differentiation and IL-17A secretion in vitro.ResultsDAPT treatment alleviated the severity of IMQ-induced mouse psoriasis-like skin inflammation and decreased the scores of erythema, scaling and thickening. HE stain reveals obviously reduced epidermal hyperplasia and dermal inflammatory cells infiltration in IMQ + DAPT-treated mice. The increased expression of splenic Th17 cell percentage, along with Notch1, Hes-1, RORγt and IL-17A mRNA and IL-17A serum concentration in IMQ-treated mice were significantly decreased when experimental mice were treated by IMQ and DAPT combinedly. Data obtained from in vitro study in IMQ-treated mice also demonstrated that blocking Notch1 signaling by DAPT can result in a dose-dependent decrease of Th17 cell proportion, mRNA expression of Notch1, Hes-1, RORγt and IL-17A as well as IL-17A secretion in splenic CD4+ T cells.ConclusionThese data suggest that Notch1 inhibition by DAPT can effectively alleviate the severity of mouse psoriasis-like skin inflammation by regulating the differentiation and function of Th17 cells, indicating that DAPT might be a potential therapeutic candidate for the treatment of psoriatic inflammation.
Highlights
IL-17-producing C D4+ T helper cells (Th17) cells and its effective cytokine IL-17A play an important role in the pathogenesis of abnormal immune responses in psoriasis
DAPT alleviates the severity of IMQ‐induced psoriasis‐like skin inflammation To evaluate the alleviatory effect of DAPT on IMQ induced psoriasis-like skin inflammation, IMQ cream was applied on the shaved back skin of BALB/c mice for 7 consecutive days with or without a daily intraperitoneal injection of 10 mg/kg/day DAPT
Similar trends in skin inflammation were observed in mice received combined-treatment with IMQ and DAPT, Table 1 Primer sequences for Notch1, Hairy/ enhancer of split-like 1 (Hes-1), IL-17A, RORγt and β-actin
Summary
Th17 cells and its effective cytokine IL-17A play an important role in the pathogenesis of abnormal immune responses in psoriasis. Notch signaling has been implicated in Th17 cell differentiation and function. Our aim was to evaluate the possible inhibitory effect of Notch signaling inhibitor, γ-secretase inhibitor DAPT, on psoriatic Th17 cell differentiation and function in a mouse model of psoriasis-like skin inflammation. Psoriatic lesion is characterized by keratinocyte hyper-proliferation with activated CD4+ lymphocytes and neutrophils infiltration in the dermis [5]. Numerous studies have shown an increased expression of Th17 cells and IL-17A in psoriatic lesion and peripheral circulation and associated with the disease severity [8, 12,13,14,15]. Suppressing Th17 response may be an effective therapeutic strategy for treating psoriasis
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