AP-1 activates KCNN4-mediated Ca2+ signaling to induce the Th1/Th17 differentiation of CD4+ cells in chronic non-bacterial prostatitis.

Abstract

The intraprostatic inflammatory infiltrate is characterized by Th1 CD4⁺ T cells, and its molecular mechanism is not well defined. This study explored the mechanisms responsible for the alteration of Th1/Th17 differentiation of CD4⁺ T cells in chronic non-bacterial prostatitis (CNP). CNP rats were induced by the administration of testosterone and 17β-estradiol. The Th1/Th17 cell percentage was increased in the prostate tissue of CNP rats, which was accompanied by increased IL-2, IFN-γ, IL-17A, and IL-22 levels. Transcriptome sequencing was performed, followed by KEGG pathway enrichment analysis. Activator protein-1 (AP-1) was enhanced in CD4⁺ T cells from CNP rats, and its inhibitor SR11302 suppressed Th1/Th17 differentiation and delayed CNP. AP-1 transcriptionally activated the expression of KCNN4, which potentiated mTORC1 in CD4⁺ T cells by enhancing Ca2⁺ signaling, thereby promoting Th1/Th17 differentiation. Rapamycin-mediated autophagy activation reversed AP-1/KCNN4/mTORC1-promoted Th1/Th17 differentiation, thereby inhibiting CNP. These results suggest that AP-1-mediated KCNN4 transcription promotes the inhibition of autophagy by mTORC1 through Ca2⁺ signaling, which supports Th1/Th17 differentiation of CD4⁺ T cells, resulting in the transformation of CNP to prostatic intraepithelial neoplasia and adenocarcinoma.