Abstract
Knee osteoarthritis (OA) is a leading cause of chronic pain and disability, yet the mechanisms linking central neuroinflammation to pain persistence remain poorly defined. This study identifies a novel perineuronal net (PNN)–microglia axis within the medial prefrontal cortex (mPFC) as a critical regulator of OA pain sensitization. Using a rat OA model, we demonstrate that high-intensity interval training (HIIT) exerts robust analgesic and disease-modifying effects, improving gait, reducing pain, and preserving cartilage integrity. HIIT markedly decreased PNN accumulation in the mPFC, driving microglial polarization away from a pro-inflammatory iNOS⁺ phenotype toward an anti-inflammatory Arg1⁺ phenotype, thereby mitigating central neuroinflammation. Importantly, pharmacological and enzymatic interventions confirmed that PNN remodeling precedes microglial phenotype switching, establishing a causal hierarchy in central inflammatory reprogramming. Parallel reductions in pro-inflammatory cytokines (IL-1β, TNF-α) and increases in IL-10 in both serum and synovial fluid underscore a systemic anti-inflammatory effect. Together, these findings reveal a previously unrecognized mechanism whereby exercise alleviates chronic pain by targeting central neuroimmune interactions, positioning HIIT as a promising non-pharmacological strategy for OA pain management through PNN-driven microglial modulation.
Data availability
Data will be made available on request. Please contact the corresponding author, Xueping Li, at lixueping6504@163.com for data access requests.
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Funding
This research was funded by the National Natural Science Foundation of China (No. 82272596).
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The conceptualization and design of the study were carried out by XpL., CsL, and XZ. Manuscript revision was completed by StZ , AlC, and XpL. Data collection, analysis, and interpretation were performed by CsL, XZ, ZqY, FZ, and KzH. The original draft of the manuscript was written by CsL, XZ, and ZqY. All authors reviewed the manuscript critically and approved the final version for submission.
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All procedures involving animals were reviewed and approved by the Animal Care and Use Committee of Nanjing Medical University (approval number: DWSY-23096400). Meanwhile, we confirm that our work was carried out in compliance with the ARRIVE guidelines.
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Lin, C., Zhang, X., Ye, Z. et al. High-intensity interval training remodels perineuronal nets in the medial prefrontal cortex to drive microglial polarization and alleviate osteoarthritis pain. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40823-w
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DOI: https://doi.org/10.1038/s41598-026-40823-w
