Inflammation is a hallmark in the human cervix remodelling. A possible candidate inducing the inflammatory driven ripening of the cervix is the matrix component heparan sulphate, which has been shown to be elevated in late pregnancy in the cervix and uterus. Heparin and a glycol-split low molecular weight heparin (gsHep) with low anticoagulant potency has been shown to enhance myometrial contraction and interleukin (IL)-8 production by cervical fibroblasts. The aim of this study was to investigate the mechanism by which heparin promotes cervical inflammation. Wild-type, Toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88) and Interferon regulatory factor 3 (IRF3)-deficient mice were treated by deposition of gsHep into the vaginas of nonpregnant mice. To identify which cells that responded to the heparin fragments, a rhodamine fluorescent construct of gsHep was used, which initially did bind to the epithelial cells and were at later time points located in the sub-mucosa. The heparin fragments induced a strong local inflammatory response in wild-type mice shown by a rapid infiltration of neutrophils and to a lesser extent macrophages into the epithelium and the underlying extracellular matrix of the cervix. Further, a marked migration into the cervical and vaginal lumen was seen by both neutrophils and macrophages. The induced mucosal inflammation was strongly reduced in TLR4- and IRF3-deficient mice. In conclusion, our findings suggest that a TLR4/IRF3-mediated innate immune response in the cervical mucosa is induced by gsHep. This low anticoagulant heparin version, a novel TLR4 agonist, could contribute to human cervical ripening during the initiation of labour.

中文翻译：

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肝素片段通过非妊娠小鼠的 Toll 样受体 4 募集免疫细胞来诱导宫颈炎症

炎症是人类子宫颈重塑的标志。诱导子宫颈炎症驱动成熟的一个可能的候选者是基质成分硫酸乙酰肝素，它已被证明在妊娠晚期在子宫颈和子宫中升高。肝素和具有低抗凝效力的乙二醇分裂低分子量肝素 (gsHep) 已被证明可增强宫颈成纤维细胞的子宫肌层收缩和白细胞介素 (IL)-8 的产生。本研究的目的是探讨肝素促进宫颈炎症的机制。野生型、Toll 样受体 4 (TLR4)、骨髓分化初级反应基因 88 (MyD88) 和干扰素调节因子 3 (IRF3) 缺陷小鼠通过将 gsHep 沉积到非妊娠小鼠的阴道中进行治疗。为了确定哪些细胞对肝素片段有反应，使用了 gsHep 的罗丹明荧光构建体，它最初确实与上皮细胞结合，并且在后来的时间点位于粘膜下层。肝素片段在野生型小鼠中诱导了强烈的局部炎症反应，表现为中性粒细胞快速浸润，巨噬细胞浸润到上皮细胞和子宫颈下层的细胞外基质中。此外，嗜中性粒细胞和巨噬细胞均观察到明显迁移到宫颈和阴道腔。在 TLR4 和 IRF3 缺陷小鼠中，诱导的黏膜炎症明显减少。总之，我们的研究结果表明，宫颈黏膜中 TLR4/IRF3 介导的先天免疫反应是由 gsHep 诱导的。这种低抗凝肝素版本，一种新型 TLR4 激动剂，