TLR8激活的miR-146a-3p是促使胎膜对细菌LPS产生炎症反应的中间信号

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-04-17 DOI:10.1111/imm.13794
Hanah M. Georges, Caterina Cassin, Mancy Tong, Vikki M. Abrahams
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引用次数: 0

摘要

早产是新生儿发病率最高的原因,通常与绒毛膜羊膜炎有关,绒毛膜羊膜炎是指胎膜(FMs)发炎/感染。绒毛膜羊膜炎的特点是中性粒细胞浸润胎膜,与中性粒细胞趋化物白细胞介素(IL)-8 和促炎细胞因子 IL-1β 水平升高有关。虽然调频可通过先天性免疫传感器(如收费样受体(TLR))对感染做出反应,但绒毛膜羊膜炎的下游机制尚未完全明了。一组新的非经典 microRNA(miR-21a、miR-29a、miR-146a-3p、Let-7b)通过激活 ssRNA 病毒传感器 TLR7 和 TLR8 发挥内源性危险信号的作用。本研究利用体外人类调频外植体系统、体内妊娠小鼠模型和人类临床样本,研究了激活 TLR7/TLR8 的 miRs 作为调频炎症介质对细菌脂多糖(LPS)反应的促炎症作用。暴露于 LPS 后,miR-146a-3p 在人类调频外植体和野生型小鼠调频中都显著增加。在早产和绒毛膜羊膜炎妇女的胎膜中,miR-146a-3p的表达也明显升高。调频IL-8和炎性体介导的IL-1β对LPS的产生依赖于miR-146a-3p和TLR4激活下游的TLR8。在野生型小鼠中,暴露于 LPS 会增加 FM IL-8 和 IL-1β 的产生并诱发早产。在TLR7-/-/TLR8-/-小鼠中,暴露于LPS能够启动早产,但不能维持早产,而且FM炎症也有所减轻。综上所述,我们证明了一种新的母胎界面信号机制,其中 TLR8 激活的 miR-146a-3p 可作为中间危险信号驱动依赖和不依赖调频炎症体的炎症机制,因此可能在绒毛膜羊膜炎和随后的早产中发挥作用。
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TLR8-activating miR-146a-3p is an intermediate signal contributing to fetal membrane inflammation in response to bacterial LPS

Preterm birth is the largest contributor to neonatal morbidity and is often associated with chorioamnionitis, defined as inflammation/infection of the fetal membranes (FMs). Chorioamnionitis is characterised by neutrophil infiltration of the FMs and is associated with elevated levels of the neutrophil chemoattractant, interleukin (IL)-8 and the proinflammatory cytokine, IL-1β. While FMs can respond to infections through innate immune sensors, such as toll-like receptors (TLRs), the downstream mechanisms by which chorioamnionitis arises are not fully understood. A novel group of non-classical microRNAs (miR-21a, miR-29a, miR-146a-3p, Let-7b) function as endogenous danger signals by activating the ssRNA viral sensors TLR7 and TLR8. In this study, the pro-inflammatory roles of TLR7/TLR8-activating miRs were examined as mediators of FM inflammation in response to bacterial lipopolysaccharide (LPS) using an in vitro human FM explant system, an in vivo mouse model of pregnancy, and human clinical samples. Following LPS exposure, miR-146a-3p was significantly increased in both human FM explants and wild-type mouse FMs. Expression of miR-146a-3p was also significantly elevated in FMs from women with preterm birth and chorioamnionitis. FM IL-8 and inflammasome-mediated IL-1β production in response to LPS was dependent on miR-146a-3p and TLR8 downstream of TLR4 activation. In wild-type mice, LPS exposure increased FM IL-8 and IL-1β production and induced preterm birth. In TLR7−/−/TLR8−/− mice, LPS exposure was able to initiate but not sustain preterm birth, and FM inflammation was reduced. Together, we demonstrate a novel signalling mechanism at the maternal-fetal interface in which TLR8-activating miR-146a-3p acts as an intermediate danger signal to drive FM inflammasome-dependent and -independent mechanisms of inflammation and, thus, may play a role in chorioamnionitis and subsequent preterm birth.

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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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