Effect of γ-secretase Inhibitor on Th17 Cell Differentiation and Function of Mouse Psoriasis-like Skin Inflammation

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2018 Mar 11

PMID 29523162

Citations 10

Authors

Lei Ma

Haibo Xue

Ruiqun Qi

Yanqin Wang

Libing Yuan

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Citing Articles

IL-17A Mediates Depressive-Like Symptoms by Inducing Microglia Activation in Psoriasiform Dermatitis Mice.

Dou Y, You J, Wang J, Li X, Lin Y, Liu B Immun Inflamm Dis. 2024; 12(12):e70092.

PMID: 39660880 PMC: 11632850. DOI: 10.1002/iid3.70092.

Notch Signaling Regulates the Function and Phenotype of Dendritic Cells in Infection.

Liu Q, Chen C, He Y, Mai W, Ruan S, Ning Y Microorganisms. 2023; 11(11).

PMID: 38004829 PMC: 10673485. DOI: 10.3390/microorganisms11112818.

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis.

Rajeh A, Cornman H, Gupta A, Szeto M, Kambala A, Oladipo O medRxiv. 2023; .

PMID: 37808834 PMC: 10557842. DOI: 10.1101/2023.09.25.23295810.

LY294002 ameliorates psoriatic skin inflammation in mice via blocking the Notch1/Hes1-PTEN/AKT/IL-17A feedback loop.

Lin Y, Zhu X, Li Y, Dou Y, Wang J, Qi R Clin Exp Immunol. 2023; 213(1):114-124.

PMID: 36840628 PMC: 10324552. DOI: 10.1093/cei/uxad025.

Notch Signaling Pathway Promotes Th17 Cell Differentiation and Participates in Thyroid Autoimmune Injury in Experimental Autoimmune Thyroiditis Mice.

Liu H, Li Y, Zhu Y, Ma L, Xue H Mediators Inflamm. 2023; 2023:1195149.

PMID: 36643586 PMC: 9839414. DOI: 10.1155/2023/1195149.

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