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Characterization of signaling pathways regulating the expression of pro-inflammatory long form thymic stromal lymphopoietin upon human metapneumovirus infection

机译:调节人偏肺病毒感染后促炎性长形式胸腺基质淋巴细胞生成素表达的信号通路的表征

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摘要

Thymic stromal lymphopoietin (TSLP) is associated with several allergic diseases including asthma. Two isoforms of TSLP exist in humans, a long form (lfTSLP) and a short form (sfTSLP), displaying distinct immunological functions. Recently, TSLP was found to be upregulated in human airway cells upon human metapneumovirus (hMPV) infection, yet it remains unclear if the two isoforms are regulated differently during hMPV infection. Importantly, the molecular mechanisms underlying hMPV-mediated TSLP induction remain undescribed. In this study, we characterized the expression and regulation of TSLP in hMPV-infected human airway cells. We demonstrated that hMPV strongly induced the expression of pro-inflammatory lfTSLP in human airway epithelial cells and lung fibroblasts. Further, knockdown of pattern recognition receptors retinoic acid-inducible gene I (RIG-I) or Toll-like receptor 3 (TLR3), as well as downstream signal transducers, abrogated hMPV-mediated lfTSLP induction. Importantly, silencing of TANK-binding kinase 1 (TBK1) also impaired hMPV-mediated lfTSLP induction, which could be attributed to compromised NF-κB activation. Overall, these results suggest that TBK1 may be instrumental for hMPV-mediated activation of NF-κB downstream RIG-I and TLR3, leading to a specific induction of lfTSLP in hMPV-infected human airway cells.
机译:胸腺基质淋巴细胞生成素(TSLP)与包括哮喘在内的多种过敏性疾病有关。 TSLP的两种同工型存在于人类中,长型(lfTSLP)和短型(sfTSLP),表现出独特的免疫功能。最近,发现人类肺炎支原体病毒(hMPV)感染后,TSLP在人气道细胞中被上调,但尚不清楚在hMPV感染期间这两种同工型是否受到不同的调节。重要的是,hMPV介导的TSLP诱导的分子机制尚未描述。在这项研究中,我们表征了hLPV感染的人气道细胞中TSLP的表达和调控。我们证明了hMPV强烈诱导人气道上皮细胞和肺成纤维细胞中促炎性lfTSLP的表达。此外,敲除模式识别受体视黄酸诱导基因I(RIG-1)或Toll样受体3(TLR3),以及下游信号转导子,废除了hMPV介导的lfTSLP诱导。重要的是,沉默TANK结合激酶1(TBK1)也损害了hMPV介导的lfTSLP诱导,这可能归因于NF-κB活化受损。总体而言,这些结果表明,TBK1可能是hMPV介导的RIG-I和TLR3下游NF-κB活化的工具,从而导致在被hMPV感染的人气道细胞中特异性诱导lfTSLP。

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