TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma
TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma
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DOI：
10.1183/13993003.01562-2020
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发表时间：
2021-05-01
影响因子：
24.3
通讯作者：
Finotto, Susetta
中科院分区：
文献类型：
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作者：
Krug, Jasmin;Kiefer, Alexander;Finotto, Susetta
引言：干扰素（IFN）反应已被报道在鼻病毒（RV）诱导的哮喘中存在缺陷。I型IFN（IFN-α/β）的异二聚体受体由IFN-α R1和IFN-α R2组成。与IFN-α/β受体复合物结合的配体在细胞内激活信号转导和转录激活因子（STAT）蛋白STAT 1和STAT 2。虽然III型IFN（IFN-λ）结合到含有IFN-λ R1和白细胞介素-10R2的不同受体，但其触发导致相同下游转录因子的激活。在这里，我们分析了RV对IFN I型和III型受体的影响，并询问了可能的Toll样受体7/8（TLR 7/8）激动剂R848介导的IFN-α R1和IFN-λ R1调节。我们测量了α干扰素外周血单个核细胞（PBMC）中IFN-β和IFN-λ及其受体水平在学龄前招募的患有和不患有哮喘的两组儿童中，用RV 1b和R848刺激的上清液和细胞团（PreDicta）和小学年龄（AGENDAS）以及来自从小鼠分离的总肺细胞的细胞上清液中。我们观察到R848诱导健康和哮喘儿童PBMC中IFN-λ R mRNA表达，但抑制IFN-α R mRNA水平。在小鼠肺细胞中，与对照组相比，RV 1b单独和与R848一起抑制T细胞中的IFN-α R蛋白，与RV 1b单独感染相比，抑制肺总IFN-λ R mRNA。在来自学龄前儿童的PBMC中，在用TLR 7/8激动剂R848处理后，IFN-α R mRNA减少，IFN-λ R1 mRNA被诱导，从而提示了在儿童哮喘中诱导抗病毒免疫应答的新途径。
Introduction: Interferon (IFN) responses have been reported to be defective in rhinovirus (RV)-induced asthma. The heterodimeric receptor of type I IFN (IFN-alpha/beta) is composed of IFN-alpha R1 and IFN-alpha R2. Ligand binding to the IFN-alpha/beta receptor complex activates signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2 intracellularly. Although type III IFN (IFN-lambda) binds to a different receptor containing IFN-lambda R1 and interleukin-10R2, its triggering leads to activation of the same downstream transcription factors. Here, we analysed the effects of RV on IFN type I and III receptors, and asked about possible Toll-like receptor 7/8 (TLR7/8) agonist R848-mediated IFN-alpha R1 and IFN-lambda R1 regulation.Methods: We measured IFN-alpha, IFN-beta and IFN-lambda and their receptor levels in peripheral blood mononuclear cell (PBMC) supernatants and cell pellets stimulated with RV1b and R848 in two cohorts of children with and without asthma recruited at pre-school age (PreDicta) and at primary school age (AGENDAS) as well as in cell supernatants from total lung cells isolated from mice.Results: We observed that R848 induced IFN-lambda R mRNA expression in PBMCs of healthy and asthmatic children, but suppressed IFN-alpha R mRNA levels. In murine lung cells, RV1b alone and together with R848 suppressed IFN-alpha R protein in T-cells compared with controls and in total lung IFN-lambda R mRNA compared with RV1b infection alone.Conclusions: In PBMCs from pre-school age children, IFN-alpha R mRNA was reduced and IFN-lambda R1 mRNA was induced upon treatment with the TLR7/8 agonist R848, thus suggesting new avenues for induction of antiviral immune responses in paediatric asthma.