School of Biomedical Science and Pharmacy, Faculty Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, New South Wales, Australia.
Asthma UK Centre, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
Am J Respir Cell Mol Biol. 2021 Mar;64(3):344-356. doi: 10.1165/rcmb.2020-0011OC.
The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells and mice we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.
2 型炎症与抗病毒免疫的相互作用是哮喘加重发病机制的基础。病毒感染可诱导哮喘中促进 2 型炎症的趋化因子 CCL17 和 CCL22；然而，调控诱导的机制尚不清楚。我们使用人类呼吸道合胞病毒 (RV) 感染人呼吸道上皮细胞和小鼠的模型，评估了调控 CCL17 和 CCL22 表达的机制。轻度至中度哮喘患者和健康志愿者接受 RV 实验性感染，并定量测定气道 CCL17 和 CCL22 蛋白。然后，我们使用气道上皮细胞和小鼠 RV 感染模型来定义 STAT6 和 NF-κB 介导的 CCL17 和 CCL22 表达调控。在 RV 感染后，哮喘患者的气道中 CCL17 和 CCL22 的表达更高，且与临床和免疫参数呈差异相关。来自哮喘患者的空气-液体界面分化的原代上皮细胞也表达更高水平的 RV 诱导的 CCL22。RV 感染增强了 2 型细胞因子诱导的 STAT6 激活。在气道上皮细胞中，2 型细胞因子和 STAT6 激活对趋化因子表达有不同的影响，增加了 CCL17 的表达并抑制了 CCL22 的表达，而 NF-κB 则促进了两种趋化因子的表达。在小鼠中，RV 感染激活了肺部 STAT6，这是 CCL17 表达所必需的，但对 CCL22 表达则不是必需的。感染 RV 的 STAT6 敲除小鼠表达了更多的 NF-κB 调节趋化因子，这与病毒的快速清除有关。因此，RV 诱导的 CCL17 和 CCL22 的上调是由 NF-κB 激活介导的，而表达则由 STAT6 差异调控。综上所述，这些发现表明，在哮喘中针对 RV 感染的 2 型 STAT6 激活的治疗靶向治疗不会阻断所有炎症途径。
