Transcription Factor Retinoid-Related Orphan Receptor γt: A Promising Target for the Treatment of Psoriasis.
Transcription Factor Retinoid-Related Orphan Receptor γt: A Promising Target for the Treatment of Psoriasis.
复制标题
转录因子视黄醇相关孤儿受体 gammat：治疗银屑病的一个有前景的靶点。
DOI：
10.3389/fimmu.2018.01210
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Zheng G
中科院分区：
文献类型：
--
作者：
Tang L;Yang X;Liang Y;Xie H;Dai Z;Zheng G
银屑病是一种常见的慢性炎症性皮肤病，危害人类健康，给全球带来重大经济负担。到目前为止，牛皮癣的治疗方法仍然不令人满意，因为它们的临床局限性和各种副作用。因此，开发一种更安全、更有效的银屑病治疗方法是当务之急。以往的研究明确表明，银屑病是一种自身免疫性疾病，主要由辅助性T细胞(Th17)介导，Th17细胞在白介素23(IL-23)的作用下高水平表达白介素17(IL-17)。IL-23-Th17-IL-17轴在银屑病发生发展中的发现，使人们对银屑病发病机制的认识发生了范式的转变。尽管抗IL-17抗体在治疗银屑病方面显示出显著的临床疗效，但与单独针对IL-17A或IL-17R的抗体相比，靶向Th17 细胞本身可能通过影响包括IL-17A、IL-17F、IL-22和粒细胞-巨噬细胞集落刺激因子在内的多种促炎细胞因子而具有最大的益处，这些细胞因子可能协同作用促进银屑病的皮肤炎症。本文就Th17型 细胞在银屑病发病机制中的重要作用作一综述。特别是，我们探索了靶向视黄醇相关孤儿受体γt(RoRγt)的小分子，RoR t是Th17Th17细胞的关键转录因子。鉴于rORγt是Th1 7 细胞分化的谱系决定转录因子，通过小分子反向激动剂靶向rorγt可能是治疗Th17介导的银屑病的一种有前途的策略。
Psoriasis, which is a common chronic inflammatory skin disease, endangers human health and brings about a major economic burden worldwide. To date, treatments for psoriasis remain unsatisfied because of their clinical limitations and various side effects. Thus, developing a safer and more effective therapy for psoriasis is compelling. Previous studies have explicitly shown that psoriasis is an autoimmune disease that is predominantly mediated by T helper 17 (Th17) cells, which express high levels of interleukin-17 (IL-17) in response to interleukin-23 (IL-23). The discovery of the IL-23–Th17–IL-17 axis in the development of psoriasis has led to the paradigm shift of understanding pathogenesis of psoriasis. Although anti-IL-17 antibodies show marked clinical efficacy in treating psoriasis, compared with antibodies targeting IL-17A or IL-17R alone, targeting Th17 cells themselves may have a maximal benefit by affecting multiple proinflammatory cytokines, including IL-17A, IL-17F, IL-22, and granulocyte-macrophage colony-stimulating factor, which likely act synergistically to drive skin inflammation in psoriasis. In this review, we mainly focus on the critical role of Th17 cells in the pathogenesis of psoriasis. Especially, we explore the small molecules that target retinoid-related orphan receptor γt (RORγt), a vital transcription factor for Th17 cells. Given that RORγt is the lineage-defining transcription factor for Th17 cell differentiation, targeting RORγt via small molecular inverse agonists may be a promising strategy for the treatment of Th17-mediated psoriasis.