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

Authors

Xianhong Liu, Boyang Li, Xianchao Dou, Wenyue Ju, Weihao Liu, Fei Zhang, Chen Jin, Yifeng Lu, Ronghao Wang, Xianguo Chen, Chaozhao Liang, Meng Zhang

Published in

Redox biology. Volume 97. Pages 104366. Sep 03, 2026. Epub Sep 03, 2026.

Abstract

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.

PMID:
42702152
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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