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

The pathogenesis of rheumatoid arthritis (RA) is complex and existing drugs have many shortcomings, including low response rates, adverse reactions, and drug resistance. A specific subtype of CD4+ T cells, T help 9 (Th9) cells, known for secreting IL-9, has been implicated in various autoimmune diseases. Th9-derived IL-9 is highly expressed in patients with RA. However, its precise relationship with RA pathogenesis is unknown. Our previous study demonstrated that PU.1, an essential transcription factor, plays a promoting role in RA pathogenesis. Here, we show for the first time that PU.1 can cause T cell abnormality in RA by promoting Th9 differentiation and IL-9 production. Our results demonstrate 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. In conclusion, we demonstrate 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.