Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University, Tianjin, 300070, China; Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300070, China.
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University, Tianjin, 300070, China.
J Autoimmun. 2024 Jul;147:103262. doi: 10.1016/j.jaut.2024.103262. Epub 2024 Jun 4.
Th17 cells mediated immune response is the basis of a variety of autoimmune diseases, including multiple sclerosis and its mouse model of immune aspects, experimental autoimmune encephalomyelitis (EAE). The gene network that drives both the development of Th17 and the expression of its effector program is dependent on the transcription factor RORγt. In this report, we showed that Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1) formed a complex with RORγt, and enhanced its transactivation activity, thus sustained the expression of the effector genes as well as RORγt in the EAE-pathogenic Th17 cells. We first found out that PIN1 was highly expressed in the samples from patients of multiple sclerosis, and the expression of Pin1 by the infiltrating lymphocytes in the central nerve system of EAE mice was elevated as well. An array of experiments with transgenic mouse models, cellular and molecular assays was included in the study to elucidate the role of Pin1 in the pathology of EAE. It turned out that Pin1 promoted the activation and maintained the effector program of EAE-pathogenic Th17 cells in the inflammation foci, but had little effect on the priming of Th17 cells in the draining lymph nodes. Mechanistically, Pin1 stabilized the phosphorylation of STAT3 induced by proinflammatory stimuli, and interacted with STAT3 in the nucleus of Th17 cells, which resulted in the increased expression of Rorc. Moreover, Pin1 formed a complex with RORγt, and enhanced the transactivation of RORγt to the +11 kb enhancer of Rorc, which enforced and maintained the expression of both Rorc and the effector program of pathogenic Th17 cells in EAE. Finally, the inhibition of Pin1, by genetic knockdown or by small molecule inhibitor, deceased the population of Th17 cells and the neuroinflammation, and alleviated the symptoms of EAE. These findings suggest that Pin1 is a potential therapeutic target for MS and other autoimmune inflammatory diseases.
Th17 细胞介导的免疫反应是多种自身免疫性疾病的基础，包括多发性硬化症及其免疫方面的小鼠模型，实验性自身免疫性脑脊髓炎（EAE）。驱动 Th17 发展和表达其效应程序的基因网络依赖于转录因子 RORγt。在本报告中，我们表明肽基脯氨酰顺/反异构酶，纽马拉交互 1（Pin1）与 RORγt 形成复合物，并增强其转录激活活性，从而维持 EAE 致病 Th17 细胞中效应基因以及 RORγt 的表达。我们首先发现，PIN1 在多发性硬化症患者的样本中高度表达，并且 EAE 小鼠中枢神经系统中的浸润淋巴细胞中 Pin1 的表达也升高。一系列实验包括转基因小鼠模型、细胞和分子测定，以阐明 Pin1 在 EAE 病理学中的作用。结果表明，Pin1 促进了炎症病灶中 EAE 致病 Th17 细胞的激活和维持效应程序，但对引流淋巴结中 Th17 细胞的初始激活影响不大。从机制上讲，Pin1 稳定了促炎刺激诱导的 STAT3 磷酸化，并在 Th17 细胞的核内与 STAT3 相互作用，导致 Rorc 的表达增加。此外，Pin1 与 RORγt 形成复合物，并增强 RORγt 对 Rorc 的+11kb 增强子的转录激活，从而加强并维持 EAE 中致病 Th17 细胞的 Rorc 和效应程序的表达。最后，通过遗传敲低或小分子抑制剂抑制 Pin1，减少了 Th17 细胞的数量和神经炎症，缓解了 EAE 的症状。这些发现表明 Pin1 是多发性硬化症和其他自身免疫性炎症性疾病的潜在治疗靶点。
