Supplementary Material for: NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

Asthma exacerbations are commonly triggered by rhinovirus infections. Viruses can activate the NFκB pathway resulting in airway inflammation and increased Th2 cytokine expression. NFκB signaling is also involved in early activation of IFNβ, which is a central mediator of antiviral responses to rhinovirus infection. Using a mouse model, this study tests our hypothesis that NFκB signaling is involved in impaired IFNβ production at viral-induced asthma exacerbations. C57BL/6 wild-type and NFκB1−/− mice were challenged with house dust mite for 3 weeks and were subsequently stimulated with the rhinoviral mimic poly(I:C). General lung inflammatory parameters and levels of the Th2 upstream cytokine IL-33 were measured after allergen challenge. At exacerbation, production of IFNβ and antiviral proteins as well as gene expression of pattern recognition receptors and IRF3/IRF7 was assessed. In the asthma exacerbation mouse model, lack of NFκB1 resulted in lower levels of IL-33 after allergen challenge alone and was associated with reduced eosinophilia. At exacerbation, mice deficient in NFκB1 exhibited enhanced expression of IFNβ and antiviral proteins. This was accompanied by increased IRF3/IRF7 expression and induction of pattern recognition receptor expression. In a human asthma dataset, a negative correlation between IRF3 and NFκB1 expression was observed. NFκB may impair antiviral responses at exacerbation, possibly by reducing expression of the transcription factors IRF3/IRF7. These findings suggest a therapeutic potential for targeting NFκB pathways at viral infection-induced exacerbations.

哮喘急性加重通常由鼻病毒（rhinovirus）感染诱发。病毒可激活核因子κB（NFκB）信号通路，引发气道炎症并上调2型辅助性T细胞（Th2）细胞因子的表达。核因子κB信号通路还参与干扰素β（IFNβ）的早期激活，而干扰素β是鼻病毒感染后抗病毒免疫应答的核心介导因子。本研究利用小鼠模型（mouse model），验证了我们的假说：在病毒诱发的哮喘急性加重过程中，核因子κB信号通路参与了干扰素β生成受损的过程。本研究对C57BL/6野生型（wild-type）小鼠与核因子κB1（NFκB1）基因敲除小鼠进行为期3周的屋尘螨（house dust mite）过敏原激发（allergen challenge），随后以鼻病毒模拟物聚肌胞苷酸（poly(I:C)）进行刺激。在过敏原激发后，研究人员检测了整体肺部炎症参数以及2型辅助性T细胞上游细胞因子白细胞介素33（IL-33）的水平。在急性加重阶段，研究人员评估了干扰素β与抗病毒蛋白的生成水平，以及模式识别受体（pattern recognition receptors）、干扰素调节因子3/干扰素调节因子7（IRF3/IRF7）的基因表达情况。在哮喘急性加重小鼠模型中，核因子κB1的缺失会使单纯过敏原激发后的白细胞介素33水平降低，并与嗜酸性粒细胞增多（eosinophilia）程度减轻相关。在急性加重阶段，核因子κB1基因敲除小鼠的干扰素β与抗病毒蛋白表达水平显著升高，同时伴随干扰素调节因子3/7的表达上调以及模式识别受体的表达诱导。在人类哮喘数据集当中，研究人员观察到干扰素调节因子3与核因子κB1的表达呈负相关。核因子κB可能通过降低转录因子（transcription factors）干扰素调节因子3/7的表达，削弱急性加重阶段的抗病毒免疫应答。上述研究结果提示，针对核因子κB信号通路进行靶向干预，有望用于治疗病毒感染诱发的哮喘急性加重。