Cell Biology Section, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA; email:
Immunogenetics Section, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:371-390. doi: 10.1146/annurev-pharmtox-010919-023711. Epub 2019 Aug 6.
Retinoic acid-related orphan receptor γt (RORγt) functions as a ligand-dependent transcription factor that regulates multiple proinflammatory genes and plays a critical role in several inflammatory and autoimmune diseases. Various endogenous and synthetic RORγ (inverse) agonists have been identified that regulate RORγ transcriptional activity, including many cholesterol intermediates and oxysterols. Changes in cholesterol biosynthesis and metabolism can therefore have a significant impact on the generation of oxysterol RORγ ligands and, consequently, can control RORγt activity and inflammation. These observations contribute to a growing literature that connects cholesterol metabolism to the regulation of immune responses and autoimmune disease. Loss of RORγ function in knockout mice and in mice treated with RORγ inverse agonists results in reduced production of proinflammatory cytokines, such as IL-17A/F, and increased resistance to autoimmune disease in several experimental rodent models. Thus, RORγt inverse agonists might provide an attractive therapeutic approach to treat a variety of autoimmune diseases.
维甲酸相关孤儿受体γt（RORγt）作为一种配体依赖性转录因子发挥作用，可调节多种促炎基因，并在多种炎症和自身免疫性疾病中发挥关键作用。已经鉴定出多种内源性和合成的 RORγ（反向）激动剂，可调节 RORγ 转录活性，包括许多胆固醇中间产物和氧化固醇。胆固醇生物合成和代谢的变化因此可能对氧化固醇 RORγ 配体的产生产生重大影响，并且可以控制 RORγt 活性和炎症。这些观察结果有助于越来越多的文献将胆固醇代谢与免疫反应和自身免疫性疾病的调节联系起来。在敲除小鼠和用 RORγ 反向激动剂处理的小鼠中失去 RORγ 功能会导致促炎细胞因子（如 IL-17A/F）的产生减少，并在几种实验性啮齿动物模型中增加对自身免疫性疾病的抵抗力。因此，RORγt 反向激动剂可能为治疗多种自身免疫性疾病提供一种有吸引力的治疗方法。
