Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
FASEB J. 2019 Oct;33(10):11469-11480. doi: 10.1096/fj.201900105RR. Epub 2019 Aug 1.
The cytokine IL-17A plays critical roles in the pathogenesis of autoimmune diseases. The frequencies of MAP kinase kinase kinase kinase 3 [also named germinal center kinase-like kinase (GLK)]-overexpressing T cells are correlated with disease severity of systemic lupus erythematosus (SLE). T-cell-specific GLK-transgenic mice develop spontaneous autoimmune responses through IL-17A. GLK signaling selectively stimulates IL-17A production in murine T cells through inducing aryl hydrocarbon receptor (AhR)-retinoic acid receptor-related orphan nuclear receptor-γt (ROR-γt) complex formation. Here, we investigated whether GLK-induced AhR-ROR-γt complex in T cells is a therapeutic target for human SLE. The population of GLKIL-17A T cells was enhanced in the peripheral blood from patients with SLE compared with that of healthy controls using flow cytometry. The receiver operating characteristic curve analysis showed that increased GLKIL-17A T-cell population in peripheral blood reflected an active stage of SLE. In addition, peripheral blood T cells from patients with SLE displayed induction of ROR-γt phosphorylation and the AhR-ROR-γt (and AhR-phosphorylated ROR-γt) complex. Moreover, we identified a small-molecule inhibitor, verteporfin, that inhibited GLK kinase activity and AhR-ROR-γt interaction. The small-molecule inhibitor verteporfin suppressed the disease severity in autoimmune mouse models and IL-17A production in T cells from patients with SLE. Collectively, the GLK-induced AhR-ROR-γt (and AhR-phosphorylated ROR-γt) complex is a therapeutic target for the GLKIL-17A subpopulation of human patients with SLE.-Chuang, H.-C., Chen, Y.-M., Chen, M.-H., Hung, W.-T., Yang, H.-Y., Tseng, Y.-H., Tan, T.-H. AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLKIL-17A subpopulation of systemic lupus erythematosus.
细胞因子白细胞介素 17A 在自身免疫性疾病的发病机制中发挥关键作用。丝裂原活化蛋白激酶激酶激酶激酶 3 [也称为生发中心激酶样激酶 (GLK)]过度表达的 T 细胞的频率与系统性红斑狼疮 (SLE) 的疾病严重程度相关。T 细胞特异性 GLK 转基因小鼠通过白细胞介素 17A 发展自发性自身免疫反应。GLK 信号通过诱导芳香烃受体 (AhR)-维甲酸受体相关孤儿核受体-γt (ROR-γt) 复合物形成，选择性地刺激小鼠 T 细胞中白细胞介素 17A 的产生。在这里，我们研究了 GLK 诱导的 T 细胞中的 AhR-ROR-γt 复合物是否是人类 SLE 的治疗靶点。与健康对照者相比，SLE 患者外周血中 GLKIL-17A T 细胞的群体通过流式细胞术增强。受试者工作特征曲线分析表明，外周血中 GLKIL-17A T 细胞群体的增加反映了 SLE 的活动期。此外，SLE 患者的外周血 T 细胞显示 ROR-γt 磷酸化和 AhR-ROR-γt（和 AhR-磷酸化 ROR-γt）复合物的诱导。此外，我们鉴定了一种小分子抑制剂，维替泊芬，其抑制 GLK 激酶活性和 AhR-ROR-γt 相互作用。小分子抑制剂维替泊芬抑制自身免疫性小鼠模型中的疾病严重程度和 SLE 患者 T 细胞中白细胞介素 17A 的产生。总的来说，GLK 诱导的 AhR-ROR-γt（和 AhR-磷酸化 ROR-γt）复合物是治疗 SLE 患者 GLKIL-17A 亚群的治疗靶点。-庄，H.-C.，陈，Y.-M.，陈，M.-H.，洪，W.-T.，杨，H.-Y.，曾，Y.-H.，谭，T.-H. AhR-ROR-γt 复合物是 MAP4K3/GLKIL-17A 亚群系统性红斑狼疮的治疗靶点。
