Hypoxia Exposure Promotes Th17 Cell Differentiation Through Activin A‐ PKM2 Axis to Exacerbate Autoimmune and Autoinflammatory Diseases

ABSTRACT Hypobaric hypoxia, a defining feature of high‐altitude environments, induces significant physiological and pathological changes in the human body. Under the disrupted homeostasis and altered disease microenvironment caused by high‐altitude conditions, the immune system exhibits distinct responses compared to those observed in low‐altitude settings. Our study investigates the impact of hypobaric hypoxia on autoimmune and autoinflammatory diseases and explores the underlying molecular mechanisms. Using an environmental simulation chamber, we subjected mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis to hypobaric hypoxia, simulating conditions at an altitude of 6000 m. Pathological analysis and flow cytometry demonstrated exacerbated disease severity and elevated Th17 cell levels. Given the established role of Th17 cells as key effector cells in autoimmune and autoinflammatory diseases, we further investigated their response through transcriptomic comparisons under normoxic and hypoxic conditions, which identified Activin A as a central regulator of hypoxia‐induced Th17 cell differentiation. In mice exposed to hypobaric hypoxia, pharmacological inhibition of Activin A significantly alleviated the severity of psoriasis. Western blotting, flow cytometry, and immunofluorescence analyses confirmed that under normoxic conditions, Activin A stimulation amplified the pathogenic Th17 cell molecular program, whereas blockade of p‐PKM2 or ERK signaling suppressed this effect. Collectively, our findings uncover a molecular mechanism whereby hypoxia‐triggered Activin A release drives pathogenic Th17 differentiation via the ERK pathway, promoting p‐PKM2 nuclear translocation and subsequent transcriptional activation of Th17 master regulators and effector cytokines. This study provides a theoretical foundation for understanding immune dysregulation at high altitudes and offers potential therapeutic strategies for mitigating high‐altitude‐associated immune disorders.