Manchester Academic Health Science Centre, Faculty of Biology Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK.
NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Exp Dermatol. 2024 Sep;33(9):e15180. doi: 10.1111/exd.15180.
Psoriasis is an incurable immune-mediated skin disease, affecting around 1%-3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4 (Jurkat) and CD8 (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4 T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA-B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.
银屑病是一种无法治愈的免疫介导性皮肤疾病，影响约 1%-3%的人群。多种证据表明，IL23 在疾病中起着关键作用。IL23 受体（IL23R）内的遗传变异增加了患银屑病的风险，专门针对 IL23 的生物疗法在治疗疾病方面显示出了很高的疗效。IL23 通过 IL23R 发挥作用，通过 STAT3 途径信号传递，介导最终导致银屑病临床表现的级联事件。鉴于 IL23R 在疾病中的重要作用，了解遗传变异对受体功能以及下游基因调控的影响非常重要。在这里，我们开发了 CD4（Jurkat）和 CD8（MyLa）T 细胞模型系统，以表达野生型风险或突变型（R381Q）保护性形式的 IL23R。在确认模型系统表达了基因/蛋白质，并对 STAT3 的磷酸化产生了差异影响之后，我们使用 RNAseq 来探索在单个时间点对两种细胞类型的基因调控的差异，并且在 Jurkat CD4 T 细胞的时间过程实验中进行了探索。这些实验发现了在表达野生型和突变型 IL23R 的细胞中差异调节的基因，包括 HLA-B、SOCS1、RUNX3、CCR5、CXCR3、CCR9、KLF3、CD28、IRF、SOCS6、TNFAIP 和 ICAM5，这些基因既与 IL23 途径有关，也与银屑病有关。这些基因有可能在疾病中定义出一个 IL23/银屑病通路，从而深入了解疾病背后的生物学机制。
