Castro Glenda, Liu Xuejun, Ngo Karen, De Leon-Tabaldo Aimee, Zhao Shanrong, Luna-Roman Rosa, Yu Jingxue, Cao Tinghua, Kuhn Robert, Wilkinson Patrick, Herman Krystal, Nelen Marina I, Blevitt Jonathan, Xue Xiaohua, Fourie Anne, Fung-Leung Wai-Ping
Janssen R&D LLC, San Diego, California, United States of America.
PLoS One. 2017 Aug 1;12(8):e0181868. doi: 10.1371/journal.pone.0181868. eCollection 2017.
RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. RORγt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORγt or RORα expression. We have generated selective small molecule RORγt modulators and they were also utilized as pharmacological tools in RORγt signature gene identification. Our results showed that RORγt controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by RORα as well albeit a weaker influence. Key Th17 genes including IL-17A, IL-17F, IL-23R, CCL20 and CCR6 were shown to be regulated by both RORγt and RORα. Our results demonstrated an overlapping role of RORγt and RORα in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. RORγt as a drug target for treatment of Th17 mediated autoimmune diseases such as psoriasis has been demonstrated recently in clinical trials. Our results suggest that RORα could be involved in same disease mechanisms and gene signatures identified in this report could be valuable biomarkers for tracking the pharmacodynamic effects of compounds that modulate RORγt or RORα activities in patients.
RORγt和RORα是视黄酸受体相关孤儿核受体（ROR）家族的转录因子。它们在Th17细胞中表达，并被认为在Th17分化中发挥作用。尽管RORγt特征基因已在小鼠Th17细胞中得到表征，但关于其在人Th17细胞中转录调控的详细信息有限，而关于RORα特征基因的了解更少，在人或小鼠T细胞中均未报道过。在本研究中，通过RNA测序分析了在Th17偏向条件下激活的人CD4 T细胞的全局基因表达。在用特异性siRNA处理以敲低RORγt或RORα表达的这些Th17细胞中鉴定出RORγt和RORα特征基因。我们已经生成了选择性小分子RORγt调节剂，它们也被用作鉴定RORγt特征基因的药理学工具。我们的结果表明，RORγt在Th17细胞中控制着非常有限数量基因的表达，其中大多数基因也受RORα调控，尽管影响较弱。包括IL-17A、IL-17F、IL-23R、CCL20和CCR6在内的关键Th17基因显示受RORγt和RORα两者调控。我们的结果证明了RORγt和RORα在人Th17细胞分化中通过调控一组特定的共同Th17基因而具有重叠作用。最近在临床试验中已证明RORγt作为治疗Th17介导的自身免疫性疾病（如银屑病）的药物靶点。我们的结果表明，RORα可能参与相同的疾病机制，本报告中鉴定的基因特征可能是用于追踪调节患者RORγt或RORα活性的化合物的药效学作用的有价值生物标志物。
