Department of Medicine, National Jewish Health, Denver, Colorado, USA.
Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
J Innate Immun. 2023;15(1):67-77. doi: 10.1159/000525315. Epub 2022 Jun 27.
Respiratory influenza A virus (IAV) infection continues to pose significant challenges in healthcare of human diseases including asthma. IAV infection in mice was shown to increase IL-33, a key cytokine in driving airway inflammation in asthma, but how IL-33 is regulated during viral infection remains unclear. We previously found that a genetic mutation in Toll-interacting protein (Tollip) was linked to less airway epithelial Tollip expression, increased neutrophil chemokines, and lower lung function in asthma patients. As Tollip is involved in maintaining mitochondrial function, and mitochondrial stress may contribute to extracellular ATP release and IL-33 secretion, we hypothesized that Tollip downregulates IL-33 secretion via inhibiting ATP release during IAV infection. Wild-type and Tollip knockout (KO) mice were infected with IAV and treated with either an ATP converter apyrase or an IL-33 decoy receptor soluble ST2 (sST2). KO mice significantly lost more body weight and had increased extracellular ATP, IL-33 release, and neutrophilic inflammation. Apyrase treatment reduced extracellular ATP levels, IL-33 release, and neutrophilic inflammation in Tollip KO mice. Excessive lung neutrophilic inflammation in IAV-infected Tollip KO mice was reduced by sST2, which was coupled with less IL-33 release. Our data suggest that Tollip inhibits IAV infection, potentially by inhibiting extracellular ATP release and reducing IL-33 activation and lung inflammation. In addition, sST2 may serve as a potential therapeutic approach to mitigate respiratory viral infection in human subjects with Tollip deficiency.
呼吸道流感病毒（IAV）感染仍然对人类疾病的医疗保健构成重大挑战，包括哮喘。研究表明，IAV 感染会增加白细胞介素 33（IL-33），这是驱动哮喘气道炎症的关键细胞因子，但病毒感染期间 IL-33 是如何调节的尚不清楚。我们之前发现， Toll 相互作用蛋白（Tollip）的基因突变与哮喘患者气道上皮 Tollip 表达减少、中性粒细胞趋化因子增加和肺功能下降有关。由于 Tollip 参与维持线粒体功能，而线粒体应激可能导致细胞外三磷酸腺苷（ATP）释放和 IL-33 分泌增加，我们假设 Tollip 通过抑制 IAV 感染期间的 ATP 释放来下调 IL-33 分泌。野生型和 Tollip 敲除（KO）小鼠感染 IAV 并接受 ATP 转化酶（apyrase）或 IL-33 诱饵受体可溶性 ST2（sST2）治疗。KO 小鼠明显减轻了体重，细胞外 ATP、IL-33 释放和中性粒细胞炎症增加。apyrase 治疗可降低 Tollip KO 小鼠的细胞外 ATP 水平、IL-33 释放和中性粒细胞炎症。sST2 可减少 IAV 感染的 Tollip KO 小鼠过度的肺中性粒细胞炎症，同时减少 IL-33 释放。我们的数据表明，Tollip 通过抑制细胞外 ATP 释放和减少 IL-33 激活和肺炎症来抑制 IAV 感染。此外，sST2 可能作为一种潜在的治疗方法，用于减轻 Tollip 缺陷的人类呼吸道病毒感染。
