Epigenetic Regulation of Immune Dysfunction in UCPPS

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Epigenetic Regulation of Immune Dysfunction in Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Anthony J Schaeffer et al

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent and debilitating condition with unclear etiology. Increasing evidence implicates immune dysregulation, yet the molecular mechanisms underlying impaired immune regulation remain poorly defined. This study investigated the role of altered immune responses within PBMC populations and DNA methylation in CP/CPPS pathogenesis.

Methods: Post-prostatic massage urine samples designated as Voided Bladder 3 (VB3) urine from CP/CPPS patients and healthy controls were analyzed for CD4+ T cell markers and lineage-defining transcription factors. DNA methylation profiling of peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells was performed using targeted methylation arrays. Functional assays evaluated IL10 production following lipopolysaccharide (LPS) stimulation, with or without azacitidine (AZA), a DNA methyltransferase inhibitor that reverses methylation-dependent gene silencing. In vivo relevance was assessed using the experimental autoimmune prostatitis (EAP) mouse model.

Results: VB3 samples from CP/CPPS patients demonstrated elevated CD4-associated transcripts and increased expression of immune-related transcription factors including RORγT. DNA methylation analysis identified differences in methylation across immune-regulatory loci including IL10, FOXP3, CD274, ITGAL, and TNF-α. PBMCs from patients exhibited diminished IL10 secretion in response to LPS, which was restored by AZA treatment. In the EAP model, recombinant IL10 administration failed to attenuate pelvic allodynia, whereas AZA significantly reduced pain sensitivity.

Conclusions: CP/CPPS is associated with epigenetic alterations in immune regulatory genes that may influence inflammatory responses. Pharmacologic inhibition of DNA methylation enhanced IL10 responses in vitro and reduced pain behaviors in vivo, supporting demethylation therapy as a potential strategy for treating chronic prostatic inflammation and pelvic pain.

Keywords: DNA methylation; FoxP3; IL10; UCPPS; chronic pain; epigenetics; immune dysregulation; pelvic pain.