Duan Runping, Xie Lihui, Li He, Wang Rong, Liu Xiuxing, Tao Tianyu, Yang Shizhao, Gao Yuehan, Lin Xianchai, Su Wenru
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China.
Biochem Pharmacol. 2022 Aug;202:115116. doi: 10.1016/j.bcp.2022.115116. Epub 2022 Jun 4.
Cyclosporine A (CsA) is a widely known immunosuppressive agent that is clinically important in autoimmune diseases owing to its selective suppression of T lymphocytes. Although it has long been recognized to inhibit T cell responses by blocking calcineurin, the potential targets and specific downstream mechanisms remain elusive. Herein, we built a comprehensive single-cell transcriptomic landscape of immune cells in the blank, untreated experimental autoimmune uveitis (EAU), and CsA-treated EAU mice. CsA reversed EAU-associated changes in cell type composition, genomic expression, cell trajectory, and cell-cell communication. We found that CsA reverses the proportion change of disease-related immune cells; regulates several crucial pathogenic factors (eg. IL1r1, CD48, and Bhlhe40) in T helper 17 cells (Th17), the transcription factor Bhlhe40 was also rescued in T helper 1 cells (Th1); and may differentiate Tregs into a state of enhanced immunosuppression. In addition, we revealed the rescued impact of CsA on all immune cell types, especially on plasma B cells differentiation and immunoglobulin secretion. Furthermore, comparisons with glucocorticoids showed that CsA might have a more premium rescue effect involved in attenuating the pathogenicity of autoreactive T cells. Our work provides a comprehensive single-cell transcriptional atlas of immune cells under CsA therapy, providing advanced insights into the mechanisms underlying CsA and a reference for developing new therapeutic strategies for autoimmune diseases.
环孢素A（CsA）是一种广为人知的免疫抑制剂，因其对T淋巴细胞的选择性抑制作用，在自身免疫性疾病的临床治疗中具有重要意义。尽管长期以来人们一直认为它通过阻断钙调磷酸酶来抑制T细胞反应，但其潜在靶点和具体的下游机制仍不明确。在此，我们构建了空白、未治疗的实验性自身免疫性葡萄膜炎（EAU）小鼠以及经CsA治疗的EAU小鼠免疫细胞的综合单细胞转录组图谱。CsA逆转了与EAU相关的细胞类型组成、基因组表达、细胞轨迹和细胞间通讯的变化。我们发现，CsA逆转了疾病相关免疫细胞的比例变化；调节了辅助性T细胞17（Th17）中的几种关键致病因子（如IL1r1、CD48和Bhlhe40），转录因子Bhlhe40在辅助性T细胞1（Th1）中也得到了挽救；并且可能使调节性T细胞（Tregs）分化为增强免疫抑制的状态。此外，我们揭示了CsA对所有免疫细胞类型的挽救作用，尤其是对浆B细胞分化和免疫球蛋白分泌的影响。此外，与糖皮质激素的比较表明，CsA在减弱自身反应性T细胞致病性方面可能具有更显著的挽救作用。我们的工作提供了CsA治疗下免疫细胞的综合单细胞转录图谱，为深入了解CsA的作用机制提供了新的视角，并为开发自身免疫性疾病的新治疗策略提供了参考。
