Effect of γ-secretase inhibitor on Th17 cell differentiation and function of mouse psoriasis-like skin inflammation.
Effect of γ-secretase inhibitor on Th17 cell differentiation and function of mouse psoriasis-like skin inflammation.
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DOI：
10.1186/s12967-018-1442-6
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发表时间：
2018-03-10
影响因子：
7.4
通讯作者：
Yuan L
中科院分区：
文献类型：
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作者：
Ma L;Xue H;Qi R;Wang Y;Yuan L
Th17细胞及其有效的细胞因子IL-17A在银屑病异常免疫反应的发病机制中起重要作用。Notch1信号通路参与Th17细胞的分化和功能。在本研究中，我们的目的是评估Notch1信号抑制剂γ-分泌酶抑制剂DAPT对银屑病样皮肤炎症小鼠模型中银屑病Th17细胞分化和功能的可能抑制作用。采用5%咪喹莫特（IMQ）外用建立小鼠银屑病样皮肤炎症模型，将实验小鼠分为对照组、咪喹莫特治疗组和咪喹莫特+ dapt治疗组。IMQ + DAPT治疗组和其他两个实验组分别腹腔注射DAPT和等量的二甲亚砜。取各组皮肤组织，用苏木精和伊红（HE）染色。采集脾脏单细胞及血清，检测Th17细胞百分比、Notch1及其靶基因Hes-1 mRNA表达水平、Th17特异性转录因子RORγt及其有效细胞因子IL-17A表达水平及血清IL-17A浓度。此外，分离imq处理小鼠脾CD4+ T细胞，用DAPT处理，进一步测定DAPT对Th17细胞分化和IL-17A分泌的体外抑制作用。DAPT治疗可减轻imq诱导的小鼠银屑病样皮肤炎症的严重程度，降低红斑、脱屑和增厚评分。HE染色显示IMQ + dapt处理小鼠表皮增生和真皮炎症细胞浸润明显减少。IMQ和DAPT联合处理小鼠脾脏Th17细胞百分比、Notch1、Hes-1、rr γt和IL-17A mRNA表达升高，IL-17A血清浓度明显降低。imq处理小鼠的体外研究数据也表明，DAPT阻断Notch1信号通路可导致脾CD4+ T细胞Th17细胞比例、Notch1、Hes-1、RORγt和IL-17A mRNA表达及IL-17A分泌呈剂量依赖性降低。这些数据表明，DAPT抑制Notch1可通过调节Th17细胞的分化和功能，有效减轻小鼠银屑病样皮肤炎症的严重程度，提示DAPT可能是治疗银屑病炎症的潜在候选药物。
Th17 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. Mouse 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. DAPT 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. These 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.
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影响因子：
--
作者：
Dorneburg C;Goß AV;Fischer M;Roels F;Barth TF;Berthold F;Kappler R;Oswald F;Siveke JT;Molenaar JJ;Debatin KM;Beltinger C
通讯作者：
Beltinger C
DOI：
10.4049/jimmunol.1003658
发表时间：
2011-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Keerthivasan S;Suleiman R;Lawlor R;Roderick J;Bates T;Minter L;Anguita J;Juncadella I;Nickoloff BJ;Le Poole IC;Miele L;Osborne BA
通讯作者：
Osborne BA
影响因子：
4.6
作者：
Lewis, B. J.;Rajpara, S.;Ormerod, A. D.
通讯作者：
Ormerod, A. D.
影响因子：
10.3
作者：
Coimbra, S.;Oliveira, H.;Santos-Silva, A.
通讯作者：
Santos-Silva, A.
影响因子：
2
作者：
Abdou, Asmaa Gaber;Maraee, Alaa Hassan;Elnaidany, Nada Farag
通讯作者：
Elnaidany, Nada Farag