Irf7 aggravates prostatitis by promoting Hif-1α-mediated glycolysis to facilitate M1 polarization

Background : Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder associated with voiding symptoms and pain in the pelvic or perineal area. Macrophages, particularly the pro-inflammatory M1 subtype, are crucial in the initiation of CP/CPPS. Interferon regulatory factor 7 (Irf7) has been implicated in promoting M1 polarization, which contributes to the onset and progression of autoimmunity. However, the role of Irf7 in the etiology and progression of CP/CPPS remains unclear. Method: We established the experimental autoimmune prostatitis (EAP) mouse model by subcutaneous injection of prostate antigen combined with complete Freund's adjuvant. We analyzed prostate, spleen, and blood samples to evaluate prostate inflammation, Irf7 expression levels, glycolysis, and M1 polarization. Our findings suggest that Irf7 exacerbates the development of EAP by enhancing Hif-1α transcription, thereby increasing glycolysis and M1 polarization. Further investigations included sh-Irf7 intervention, Dimethyloxalylglycine (a Hif-1α agonist), and in vitro M1 polarization experiments. We also employed ChIP assays, dual-luciferase reporter assays, and q-PCR to explore if Irf7 could directly interact with the Hif-1α promoter in macrophages. Results : In the EAP mouse and cell models, elevated Irf7 expression was observed in inflamed tissues and cells. Reducing Irf7 expression decreased M1 cell glycolysis by inhibiting the nuclear translocation of Hif-1α, thus mitigating M1 cell polarization. Additionally, Irf7 was identified as a transcription factor in the cytoplasm that regulates Hif-1α transcription by interacting with its promoter in macrophages, confirmed through ChIP and dual-luciferase assays. Co-culturing macrophage cells with 3T3 fibroblasts with reduced Irf7 levels resulted in decreased fibrosis, and a significant reduction in prostate tissue fibrosis was noted in mice with Irf7 knockdown. Conclusion: Our findings indicate that Irf7 can contribute to the development and progression of CP/CPPS by promoting glycolysis, which can enhance both M1 polarization as well as interstitial fibrosis in the prostate. This process was found to be mediated by the upregulation of Hif-1α transcription, presenting new potential therapeutic targets for managing CP/CPPS.