Positive feedback loop PU.1-IL9 in Th9 promotes rheumatoid arthritis development

作者：Jiajie Tu, Weile Chen, Wei Huang, Xinming Wang, Yilong Fang, Xuming Wu, Huiru Zhang, Chong Liu, Xuewen Tan, Xiangling Zhu, Huihui Wang, Dafei Han, Yizhao Chen, Anqi Wang, Yuanyuan Zhou, Zimeng Xue, Hui Xue, Shangxue Yan, Lingling Zhang, Zhenbao Li, Chunlan Yang, Yujie Deng, Shihao Zhang, Zhu Chen, Wei Wei · 发表于：Annals of the Rheumatic Diseases · 年份：2024 · DOI：10.1136/ard-2024-226067 · 被引用次数：22 · 研究领域：Psoriasis: Treatment and Pathogenesis、Rheumatoid Arthritis Research and Therapies、T-cell and B-cell Immunology

OBJECTIVES: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified. METHODS: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR. RESULTS: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its ...