TENS alleviates CP/CPPS-related inflammation and pain by modulating Kir2.1-dependent macrophage polarization

Introduction: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains a challenging urological condition. This study investigated the therapeutic potential of transcutaneous electrical nerve stimulation (TENS) in experimental autoimmune prostatitis (EAP) and explored its underlying mechanisms.

Methods: Prostate tissue samples from 26 benign prostatic hyperplasia (BPH) patients were collected at Shantou Central Hospital and analyzed for M1/M2 macrophage infiltration using immunohistochemistry (IHC). In animal experiments, 24 male Sprague-Dawley rats were divided into control (n = 4), EAP (n = 7), and TENS treatment groups (n = 13; EAP + 1 Hz, n = 3; EAP + 2 Hz, n = 3; EAP + 4 Hz, n = 7). EAP was induced via prostate antigen injections, and TENS (1-4 Hz) was applied. In cell experiments, RAW264.7 macrophages were grouped into control, LPS-stimulated, electrical stimulation (ES)-treated (0.1-0.5 V/cm), and ES + pharmacological intervention (zacopride/probenecid) groups to study repolarization mechanisms.

Results: In BPH tissues, the M1/M2 macrophage ratio positively correlated with inflammation severity. In EAP rats, 4 Hz TENS significantly alleviated pelvic pain, reduced proinflammatory cytokine expression, and reversed histopathological damage. TENS promoted macrophage repolarization toward the M2 phenotype. ES in vitro similarly induced M1-to-M2 repolarization, which was associated with decreased inwardly rectifying K+ channel Kir2.1 (Kir2.1) and Transient receptor potential vanilloid 2 (TRPV2) expression, membrane depolarization, reduced CA²⁺ influx, and a shift from NF-κB/STAT1 to STAT6 signaling. Agonists of Kir2.1 TRPV2 reversed these effects.

Conclusion: TENS alleviates CP/CPPS by promoting M1-to-M2 macrophage repolarization, representing a promising therapeutic strategy.