T cell-derived CCL5 drives macrophage immunometabolic remodeling in chronic prostatitis via the CCR5-ERK-PKM2/HIF-1α axis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects millions of men, yet the immune circuits that sustain sterile prostatic inflammation and pain remain poorly defined. Here we identify a T cell-macrophage metabolic signaling axis that drives chronic prostatitis. Integrated analysis of mouse experimental autoimmune prostatitis, chronically inflamed human prostate tissue, single-cell transcriptomes and spatial profiles revealed a population of glycolytic, HIF-1α-activated inflammatory macrophages enriched in diseased prostate niches. T cell-derived CCL5 was markedly induced and spatially positioned adjacent to CCR5+ macrophages, where it licensed M1-like polarization, glycolytic remodeling and inflammatory transcription. Using T cell-specific Ccl5 knockout mice, we established CCL5 as a genetic driver of macrophage inflammation, prostate tissue injury and pelvic pain hypersensitivity, and these pathogenic features were further suppressed by CCL5 neutralization or pharmacological CCR5 blockade. Mechanistically, rmCCL5 stimulation promoted CCR5-sensitive ERK1/2 activation, PKM2 Ser37 phosphorylation and nuclear accumulation, enhanced the PKM2-HIF-1α interaction, and increased HIF-1α occupancy at the Il1b and Nos2 promoters. Targeting ERK1/2, PKM2 remodeling or HIF-1α collapsed this program and protected against prostatitis pathology. Together, these findings show how T cell-derived chemokine signals are translated into macrophage metabolic reprogramming and persistent inflammatory activation, nominating the CCL5-CCR5-ERK-PKM2/HIF-1α pathway as a genetically validated and pharmacologically tractable therapeutic axis in CP/CPPS.