Targeting the PNN–Microglia Axis: Evidence for Exercise-Induced Central and Peripheral Anti-Inflammatory Reprogramming in Osteoarthritis

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.