Increased intracellular Cl− concentration mediates Trichomonas vaginalis-induced inflammation in the human vaginal epithelium

[Display omitted] •Trichomonas vaginalis triggered inflammation and an increase in [Cl−]i in the vaginal epithelium.•Cysteine proteases were implicated in T. vaginalis-elicited down-regulation of CFTR.•There was increased [Cl−]i mediated vaginal epithelial inflammation via SGK1 activation.•Up-regulation of phosphodiesterase 4 degraded cAMP and promoted disequilibrium in [Cl−]i. Trichomonas vaginalis is a primary urogenital parasite that causes trichomoniasis, a common sexually transmitted disease. As the first line of host defense, vaginal epithelial cells play critical roles in orchestrating vaginal innate immunity and modulate intracellular Cl− homeostasis via the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that plays positive roles in regulating nuclear factor-κB (NF-κB) signalling. However, the association between T. vaginalis infection and intracellular Cl− disequilibrium remains elusive. This study showed that after T. vaginalis infection, CFTR was markedly down-regulated by cysteine proteases in vaginal epithelial cells. The intracellular Cl− concentration ([Cl−]i) was consequently elevated, leading to NF-κB signalling activation via serum- and glucocorticoid-inducible kinase-1. Moreover, heightened [Cl−]i and activated NF-κB signalling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP through NF-κB-mediated up-regulation of phosphodiesterase 4. The results conclusively revealed that the intracellular Cl− of the human vaginal epithelium could be dynamically modulated by T. vaginalis, which contributed to mediation of epithelial inflammation in the human vagina.