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