Identification of novel mechanisms involved in generating localized vulvodynia pain

Abstract

Objective Our goal was to gain a better understanding of the inflammatory pathways affected during localized vulvodynia, a poorly understood, common, and debilitating condition characterized by chronic pain of the vulvar vestibule. Methods In a control matched study, primary human fibroblast strains were generated from biopsies collected from localized provoked vulvodynia (LPV) cases and age and race-matched controls. We then examined intracellular mechanisms by which these fibroblasts recognize pathogenic Candida albicans; >70% of vulvodynia patients report the occurrence of prior chronic Candida infections, which is accompanied by localized inflammation and elevated production of pro-inflammatory/pain-associated interleukin 6 (IL-6) and prostaglandin E2 (PGE2). We focused on examining the signaling pathways involved in recognition of yeast components that are present and abundant during chronic infection. Results Dectin-1, a surface receptor that binds C. albicans cell wall glucan, was significantly elevated in vestibular versus external vulvar cells (from areas without pain) in both cases and controls, while its abundance was highest in LPV cases. Blocking Dectin-1 signaling significantly reduced pain-associated IL-6 and PGE2 production during the response to C. albicans. Furthermore, LPV patient vestibular cells produced inflammatory mediators in response to low numbers of C. albicans cells, while external vulvar fibroblasts were nonresponsive. Inhibition of NFκB (pro-inflammatory transcription factor) nearly abrogated IL-6 and PGE2 production induced by C. albicans, in keeping with observations that Dectin-1 signals through the NFκB pathway. Conclusion These findings implicate that a fibroblast-mediated pro-inflammatory response to C. albicans contributes to the induction of pain in LPV cases. Targeting this response may be an ideal strategy for the development of new vulvodynia therapies.

A Role for Bradykinin Signaling in Chronic Vulvar Pain

“…Our recently published work also supports a Candida- LPV association; fibroblasts isolated from sites of LPV allodynia respond strongly to C. albicans and other vaginal fungal pathogens through the production of proinflammatory mediators (e.g. interleukin-6; IL-6 and prostaglandin E 2 ; PGE 2 ) 20, 23 . We also have evidence that other inflammatory triggers (not specific to fungal infection) stimulate the production of proinflammatory mediators 25 .…”

“…Tissue was sampled for fibroblast strain development from sites as diagrammed previously 23, 25 . A total of 3 paired case (vulvar vestibule and external vulva) and 3 paired control fibroblast strains (12 total) were used in this study, which were also used in a preceeding study 20 .…”

“…Presently, therapeutics for vulvodynia manage the symptoms of LPV, but none target the underlying inflammatory origins of disease 30, 32, 63 . In a previous study, we demonstrated that vestibular fibroblasts derived from LPV patients at sites with low pain thresholds express elevated levels of the Dectin-1 receptor, which is responsible for recognizing fungal cell wall-derived β-glucan 20 . Exposure to fungal cell wall components or fungi resulted in a potent inflammatory response, which was comparatively stronger in patient fibroblasts isolated from pain versus non-pain sites 20 .…”

“…In a previous study, we demonstrated that vestibular fibroblasts derived from LPV patients at sites with low pain thresholds express elevated levels of the Dectin-1 receptor, which is responsible for recognizing fungal cell wall-derived β-glucan 20 . Exposure to fungal cell wall components or fungi resulted in a potent inflammatory response, which was comparatively stronger in patient fibroblasts isolated from pain versus non-pain sites 20 . However, blocking Dectin-1 signaling only partially ameliorated IL-6 and PGE 2 release, implying that other receptors/mechanisms contribute to proinflammatory mediator release, and likely pain 20 .…”

“…Exposure to fungal cell wall components or fungi resulted in a potent inflammatory response, which was comparatively stronger in patient fibroblasts isolated from pain versus non-pain sites 20 . However, blocking Dectin-1 signaling only partially ameliorated IL-6 and PGE 2 release, implying that other receptors/mechanisms contribute to proinflammatory mediator release, and likely pain 20 . Therefore, a broader understanding of the inflammatory pathways that might affect LPV are necessary to design more effective therapeutic agents that will target the underlying biological cause(s) of disease.…”