Darville Toni, Sun Xuejun, Zhang Yu, O'Connell Catherine M, Mokashi Neha, Tang Weiming, Bhardwaj Aakash, Duncan Bryce, Andrews Charles W, Weisenfeld Harold, Zheng Xiaojing
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
bioRxiv. 2025 Jun 26:2025.06.23.661210. doi: 10.1101/2025.06.23.661210.
genital tract infection is linked to severe reproductive complications in women, including ectopic pregnancy, infertility, and adverse pregnancy outcomes. Mouse models of infection suggest that chlamydia-induced dysregulation of microRNAs (miRNAs) can drive harmful cytokine responses, pathogenic epithelial-mesenchymal transition (EMT), and fibrosis. To investigate these mechanisms in humans, we profiled miRNA and mRNA expression in endometrial biopsies from women with endometrial infection (Endo+) and compared them to profiles from women with cervix-only infection (Endo-) or no infection. Ingenuity Pathway Analysis (IPA) revealed that Endo+ tissues had upregulated genes associated with innate and adaptive immune response pathways, as well as EMT regulation, while downregulated genes were linked to cell cycle control. An integrative miRNA-mRNA analysis, which combined a review of published miRNA regulation in human infections and immune responses with IPA's miRNA target filter, identified differentially expressed miRNAs that modulate these pathways in the endometrium of Endo+ women. Functional annotation of these miRNAs showed a predominance of downregulated miRNAs that typically suppress EMT and regulatory T cell (Treg) differentiation, along with miRNAs that usually enhance Th17 responses. Comparisons with previously identified mRNA pathways in blood samples from women with endometrial infection indicated that alterations in TGF-β signaling and EMT were specific to the endometrium. Overall, the miRNA-mRNA interactions inferred from Endo+ tissue suggest increased activity in TGF-β pathways that promote enhanced EMT and Treg differentiation, while reducing Th17 activation. These changes highlight a dual potential for promoting tissue scarring while dampening inflammatory responses that could otherwise limit infection.
生殖道感染与女性严重的生殖并发症有关，包括异位妊娠、不孕和不良妊娠结局。感染的小鼠模型表明，衣原体诱导的微小RNA（miRNA）失调可引发有害的细胞因子反应、致病性上皮-间质转化（EMT）和纤维化。为了在人类中研究这些机制，我们分析了子宫内膜感染女性（Endo+）子宫内膜活检组织中的miRNA和mRNA表达，并将其与仅宫颈感染女性（Endo-）或未感染女性的表达谱进行比较。 Ingenuity通路分析（IPA）显示，Endo+组织中与先天和适应性免疫反应通路以及EMT调节相关的基因上调，而下调的基因与细胞周期控制有关。综合miRNA-mRNA分析结合了已发表的人类感染和免疫反应中miRNA调节的综述以及IPA的miRNA靶标筛选，确定了在Endo+女性子宫内膜中调节这些通路的差异表达miRNA。这些miRNA的功能注释显示，下调的miRNA占主导地位，这些miRNA通常抑制EMT和调节性T细胞（Treg）分化，同时还有通常增强Th17反应的miRNA。与先前在子宫内膜感染女性血液样本中鉴定的mRNA通路进行比较表明，TGF-β信号通路和EMT的改变是子宫内膜特有的。总体而言，从Endo+组织推断的miRNA-mRNA相互作用表明，TGF-β通路活性增加，促进EMT和Treg分化增强，同时降低Th17激活。这些变化突出了促进组织瘢痕形成同时抑制可能限制感染的炎症反应的双重潜力。
