1. Positive feedback loop PU.1-IL9 in Th9 promotes rheumatoid arthritis development.
- Author
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Tu J, Chen W, Huang W, Wang X, Fang Y, Wu X, Zhang H, Liu C, Tan X, Zhu X, Wang H, Han D, Chen Y, Wang A, Zhou Y, Xue Z, Xue H, Yan S, Zhang L, Li Z, Yang C, Deng Y, Zhang S, Zhu C, and Wei W
- Subjects
- Animals, Humans, Mice, T-Lymphocytes, Helper-Inducer immunology, Male, Female, Up-Regulation, Receptors, Interleukin-9 genetics, Receptors, Interleukin-9 metabolism, Signal Transduction, Interleukin-9 metabolism, Interleukin-9 genetics, Interleukin-9 immunology, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid metabolism, Arthritis, Rheumatoid immunology, Trans-Activators genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Mice, Knockout, Arthritis, Experimental metabolism, Arthritis, Experimental immunology, Arthritis, Experimental genetics, Arthritis, Experimental pathology, Feedback, Physiological
- Abstract
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 transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway., Conclusions: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)
- Published
- 2024
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