Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia
Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia
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DOI：
10.1097/lgt.0000000000000364
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发表时间：
2018-01-01
影响因子：
3.7
通讯作者：
Phipps, Richard P.
中科院分区：
文献类型：
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作者：
Falsetta, Megan L.;Foster, David C.;Phipps, Richard P.
目的：局限性外阴疼痛(LPV)困扰着美国约8%的女性，给女性带来巨大的经济、身体和心理负担。患有LPV的女性会在外阴前庭(紧靠阴道开口周围的区域)感受到强烈的疼痛。我们已经确定了与LPV发展有关的机制，即外阴成纤维细胞对促炎刺激做出反应，以维持导致疼痛的炎症反应。然而，这些机制还没有完全阐明。因此，我们探讨了Toll样受体(Toll-like Receptor，TLRs)的作用，Toll样受体是一类对微生物攻击快速反应的先天免疫受体。材料和方法：为了确定外阴成纤维细胞是否表达TLRs，以及这些受体是否参与了LPV中促炎症介质的产生和疼痛，我们检测了痛性前庭区和非痛性外阴区成纤维细胞中Toll样受体的表达和先天免疫反应。结果：人外阴成纤维细胞表达功能性TLRs，触发与慢性疼痛相关的炎症介质的产生。我们将重点放在TLR-7-咪喹莫特的促炎作用上，因为TLR-7的配体咪喹莫特在治疗人类乳头瘤病毒相关疾病时可能会加剧女性的疼痛。结论：人外阴成纤维细胞表达广泛的TLRs(这是一个新发现)。在LPV病例的前庭成纤维细胞中，观察到TLR介导的致炎反应显著增加，关于咪喹莫特-TLR7的相互作用，慢性前庭疼痛和炎症的发展可能是外阴人乳头瘤病毒相关疾病治疗的后遗症。抑制对一系列病原体相关分子模式的增强的TLR相关的先天免疫反应可能是治疗外阴疼痛的一种新的/有效的方法。
Objectives: Localized provoked vulvodynia (LPV) afflicts approximately 8% of women in the United States and represents a huge financial, physical, and psychological burden. Women with LPV experience intense pain localized to the vulvar vestibule (area immediately surrounding vaginal opening). We have identified mechanisms involved in the development of LPV whereby vulvar fibroblasts respond to proinflammatory stimuli to perpetuate an inflammatory response that causes pain. However, these mechanisms are not fully elucidated. Therefore, we explored the role of toll-like receptors (TLRs), a class of innate immune receptors that rapidly respond to microbial assaults.Materials and Methods: To determine whether TLRs are expressed by vulvar fibroblasts and whether these contribute to proinflammatory mediator production and pain in LPV, we examined TLR expression and innate immune responses in fibroblasts derived from painful vestibular regions compared with nonpainful external vulvar regions.Results: Human vulvar fibroblasts express functional TLRs that trigger production of inflammatory mediators associated with chronic pain. We focused on the TLR-7-imiquimod proinflammatory interaction, because imiquimod, a ligand of TLR-7, may exacerbate pain in women during treatment of human papillomavirus-associated disease.Conclusions: Human vulvar fibroblasts express a broad spectrum of TLRs (a new finding). A significantly higher TLR-mediated proinflammatory response was observed in LPV case vestibular fibroblasts, and with respect to the imiquimod-TLR 7 interaction, development of chronic vestibular pain and inflammation may be a possible sequelae of treatment of vulvar human papillomavirus-associated disease. Suppressing enhanced TLR-associated innate immune responses to a spectrum of pathogen-associated molecular patterns may represent a new/effective therapeutic approach for vulvodynia.