Chlamydial YAP activation in host endocervical epithelial cells mediates pro-fibrotic paracrine stimulation of fibroblasts.
Chlamydial YAP activation in host endocervical epithelial cells mediates pro-fibrotic paracrine stimulation of fibroblasts.
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DOI：
10.1128/msystems.00904-23
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发表时间：
2023-12-21
期刊：
影响因子：
6.4
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中科院分区：
文献类型：
--
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沙眼衣原体感染女性生殖道可产生严重的纤维化后遗症，包括输卵管因素不孕和宫外孕。虽然感染明显介导宿主细胞中的促纤维化反应，但尚不清楚上生殖道的内在特性是否加剧衣原体纤维化。上生殖道相对无菌的环境容易对感染产生促炎反应，可能会加剧纤维化；然而，亚临床沙眼衣原体感染仍然会出现纤维化相关的后遗症。在这里，我们比较了原代人宫颈和阴道上皮细胞的感染相关和稳态基因表达。在前者中，我们观察到纤维化相关信号因子（例如 TGFA、IL6、IL8 和 IL20）的基线表达增强和感染介导的诱导，这意味着衣原体相关促纤维化信号的易感性。转录因子富集分析确定了 YAP 的调节靶标，YAP 是一种由宫颈上皮细胞感染诱导的转录辅助因子，但不是阴道上皮细胞感染。感染诱导的YAP靶基因包括分泌的成纤维细胞激活信号因子；因此，我们开发了一种体外模型，涉及感染的宫颈内膜上皮细胞与未感染的成纤维细胞的共培养。共培养增强了 I 型胶原的成纤维细胞表达，并促进了 α-平滑肌肌动蛋白的可重复（尽管统计上不显着）诱导。成纤维细胞胶原诱导对受感染上皮细胞中 siRNA 介导的 YAP 敲低敏感，表明衣原体 YAP 激活参与了这种效应。总的来说，我们的结果提出了衣原体引发纤维化的新机制，其中感染介导的宿主 YAP 诱导促进了促纤维化的细胞间通讯。因此，宫颈上皮细胞中衣原体 YAP 的激活是该组织对纤维化易感性的决定因素。沙眼衣原体慢性或反复感染女性上生殖道可导致严重的纤维化后遗症，包括输卵管因素不孕和宫外孕。然而，这种效应背后的分子机制尚不清楚。在本报告中，我们定义了一个针对上生殖道沙眼衣原体感染的转录程序，确定了宿主 YAP（一种促纤维化转录辅助因子）的组织特异性诱导作为感染介导的纤维化基因表达的潜在驱动因素。此外，我们发现受感染的宫颈管上皮细胞刺激成纤维细胞产生胶原蛋白，并表明衣原体诱导 YAP 参与了这种效应。我们的结果定义了感染通过旁分泌信号介导组织水平纤维化病理学的机制，并将 YAP 确定为预防女性生殖道衣原体相关疤痕形成的潜在治疗靶点。
Infection of the female genital tract by Chlamydia trachomatis can produce severe fibrotic sequelae, including tubal factor infertility and ectopic pregnancy. While infection demonstrably mediates a pro-fibrotic response in host cells, it remains unclear if intrinsic properties of the upper genital tract exacerbate chlamydial fibrosis. The relatively sterile environment of the upper genital tract is primed for a pro-inflammatory response to infection, potentially enhancing fibrosis; however, subclinical C. trachomatis infections still develop fibrosis-related sequelae. Here, we compare infection-associated and steady-state gene expression of primary human cervical and vaginal epithelial cells. In the former, we observe enhanced baseline expression and infection-mediated induction of fibrosis-associated signal factors (e.g., TGFA, IL6, IL8, and IL20), implying predisposition to Chlamydia-associated pro-fibrotic signaling. Transcription factor enrichment analysis identified regulatory targets of YAP, a transcriptional cofactor induced by infection of cervical epithelial cells, but not vaginal epithelial cells. YAP target genes induced by infection include secreted fibroblast-activating signal factors; therefore, we developed an in vitro model involving coculture of infected endocervical epithelial cells with uninfected fibroblasts. Coculture enhanced fibroblast expression of type I collagen, as well as prompting reproducible (albeit statistically insignificant) induction of α-smooth muscle actin. Fibroblast collagen induction was sensitive to siRNA-mediated YAP knockdown in infected epithelial cells, implicating chlamydial YAP activation in this effect. Collectively, our results present a novel mechanism of fibrosis initiated by Chlamydia, wherein infection-mediated induction of host YAP facilitates pro-fibrotic intercellular communication. Chlamydial YAP activation in cervical epithelial cells is thus a determinant of this tissue’s susceptibility to fibrosis. Chronic or repeated infection of the female upper genital tract by C. trachomatis can lead to severe fibrotic sequelae, including tubal factor infertility and ectopic pregnancy. However, the molecular mechanisms underlying this effect are unclear. In this report, we define a transcriptional program specific to C. trachomatis infection of the upper genital tract, identifying tissue-specific induction of host YAP—a pro-fibrotic transcriptional cofactor—as a potential driver of infection-mediated fibrotic gene expression. Furthermore, we show that infected endocervical epithelial cells stimulate collagen production by fibroblasts and implicate chlamydial induction of YAP in this effect. Our results define a mechanism by which infection mediates tissue-level fibrotic pathology via paracrine signaling and identify YAP as a potential therapeutic target for the prevention of Chlamydia-associated scarring of the female genital tract.
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影响因子：
8.8
作者：
Alder O;Cullum R;Lee S;Kan AC;Wei W;Yi Y;Garside VC;Bilenky M;Griffith M;Morrissy AS;Robertson GA;Thiessen N;Zhao Y;Chen Q;Pan D;Jones SJM;Marra MA;Hoodless PA
通讯作者：
Hoodless PA
影响因子：
56.3
作者：
Davies, Bethan;Turner, Katy M. E.;Westh, Henrik
通讯作者：
Westh, Henrik
DOI：
10.4049/jimmunol.1103032
发表时间：
2012-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gondek DC;Olive AJ;Stary G;Starnbach MN
通讯作者：
Starnbach MN
DOI：
10.1111/aji.12230
发表时间：
2014-06
期刊：
American journal of reproductive immunology (New York, N.Y. : 1989)
影响因子：
--
作者：
Anderson DJ;Marathe J;Pudney J
通讯作者：
Pudney J
影响因子：
3.7
作者：
Govender Y;Avenant C;Verhoog NJ;Ray RM;Grantham NJ;Africander D;Hapgood JP
通讯作者：
Hapgood JP