Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation
Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation
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靶向 RORγt 的小分子通过抑制 Th17 细胞分化来抑制自身免疫性疾病
DOI：
10.1038/s41419-020-02891-2
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发表时间：
2020-08-22
影响因子：
9
通讯作者：
Hou, Shengping
中科院分区：
文献类型：
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作者：
Tan, Jun;Liu, Huan;Hou, Shengping
Th 17细胞是一种以表达转录因子“视黄酸受体相关孤儿受体γ-t”（ROR γ t）为特征的淋巴细胞亚群，在自身免疫性疾病的发病机制中起重要作用。本研究旨在发现ROR γ t的新型非甾体小分子反向激动剂，并确定其对自身免疫性疾病的作用。使用基于结构的虚拟筛选（SBVS）来寻找靶向ROR γ t的化合物。流式细胞仪检测Th 17细胞分化情况。向经历实验性自身免疫性葡萄膜炎（EAU）、实验性自身免疫性脑脊髓炎（EAE）或1型糖尿病的小鼠腹膜内施用反向激动剂。通过临床或组织病理学评分评价反向激动剂的作用。在筛选的130万种化合物中，发现CQMU 151和CQMU 152抑制Th 17细胞分化而不影响Th 1和Treg谱系的分化（均P = 0.001）。这些化合物还降低了EAU的严重程度（P = 0.01和0.013），并且功能研究表明，它们降低了小鼠视网膜中Th 17细胞的数量和IL-17（Th 17）的表达，但不降低IFN-γ（Th 1）和TGF-β（Treg）的表达。进一步的研究表明，这些化合物可以通过减少IL-17/IL-6/STAT 3的正反馈环来减少p-STAT 3的表达。这些化合物还通过上调紧密连接蛋白的表达来降低受损的血-视网膜屏障功能。这些化合物也被发现可以降低EAE和1型糖尿病的严重程度。我们的研究结果表明，ROR γ t反向激动剂可以抑制自身免疫性疾病的发展，并可能为治疗Th 17介导的免疫性疾病提供新的线索。
Th17 cells, a lymphocyte subpopulation that is characterized by the expression of the transcription factor "retinoic acid receptor-related orphan receptor gamma-t" (ROR gamma t), plays an important role in the pathogenesis of autoimmune disease. The current study was set up to discover novel and non-steroidal small-molecule inverse agonists of ROR gamma t and to determine their effects on autoimmune disease. Structure-based virtual screening (SBVS) was used to find compounds targeting ROR gamma t. Flow cytometry was used to detect the Th17 cell differentiation. Inverse agonists were intraperitoneally administered to mice undergoing experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE) or type 1 diabetes. The effects of the inverse agonists were evaluated by clinical or histopathological scoring. Among 1.3 million compounds screened, CQMU151 and CQMU152 were found to inhibit Th17 cell differentiation without affecting the differentiation of Th1 and Treg lineages (bothP = 0.001). These compounds also reduced the severity of EAU (P = 0.01 and 0.013) and functional studies showed that they reduced the number of Th17 cell and the expression of IL-17(Th17), but not IFN-gamma(Th1) and TGF-beta(Treg) in mouse retinas. Further studies showed that these compounds may reduce the expression of p-STAT3 by reducing the positive feedback loop of IL-17/IL-6/STAT3. These compounds also reduced the impaired blood-retinal barrier function by upregulating the expression of tight junction proteins. These compounds were also found to reduce the severity of EAE and type 1 diabetes. Our results showed that ROR gamma t inverse agonists may inhibit the development of autoimmune diseases and may provide new clues for the treatment of Th17-mediated immune diseases.