Tollip inhibits IL-33 signaling during airway influenza virus infection

项目2的目标是确定Tollip如何保护呼吸道免受病毒感染和IL-33信号的影响 哮喘加重。与呼吸道病毒感染(如流感)相关的哮喘加重 由于缺乏有效的抗病毒治疗，(病毒)仍然是一个巨大的挑战。这些病毒主要感染 人呼吸道上皮细胞。病毒感染、组织损伤和炎症的潜在机制还没有 已经很好地理解了。在这个项目中，我们将重点研究多功能免疫调节剂Toll的作用- 相互作用蛋白(Tollip)在病毒感染，特别是甲型流感病毒(IAV)中的作用，因为它代表更严重的 哮喘病毒感染的一种形式。参与哮喘发病机制的关键细胞因子之一是IL-33，它是 由呼吸道上皮细胞和其他结构细胞表达，并可在以下组织损伤过程中释放 病毒感染。IL-33通过与膜结合受体ST2L结合，发挥多种功能 在哮喘发病机制中的作用。通过使用Tollip基因敲除的IAV感染小鼠模型，我们发现Tollip 缺乏会增加肺部病毒载量，体重减轻，呼吸道中性粒细胞炎症，更重要的是 裂解的IL-33释放到气道腔。Tollip缺乏症延迟性呼吸道上皮损伤 愈合，减少IL-33诱骗受体可溶性ST2(Sst2)的产生，增加粘液杯状细胞 IL-13刺激的呼吸道上皮细胞表达ST2L我们在此假设托利普是在保护 通过抑制IL-33信号来对抗哮喘的病毒性加重。在目标1中，我们将定义 Tollip在2型炎症呼吸道病毒感染过程中IL-33释放和激活的检测 通过促进上皮损伤愈合和减少ATP释放来保护呼吸道上皮损伤 在呼吸道病毒感染期间，人呼吸道上皮细胞和小鼠的2型炎症模型。在……里面 目的2，我们将确定Tollip在病毒感染合并2型炎症的呼吸道中对Sst2的调节 检测Tollip是否增加ST2近端启动子的转录活性以部分诱导Sst2表达 通过抑制STAT3的激活。在目标3中，我们将确定Tollip在病毒感染过程中对ST2L的调节 通过测试Tollip是否通过减少黏液杯状细胞来抑制ST2L的表达 IL-13/IL-33和IAV对呼吸道上皮细胞的影响。项目2中拟议的研究将揭示 遗传和/或环境因素所致的Tollip缺乏促进呼吸道损伤和 2型炎症环境中的炎症。减少释放的ATP功能/活动的SST2或代理可以服务于 作为纠正Tollip缺陷介导的IL-33信号在病毒期间在呼吸道的有害影响的一种治疗方法 哮喘加重。

The goal of Project 2 is to determine how Tollip protects airways from viral infection and IL-33 signaling during asthma exacerbations. Asthma exacerbations associated with respiratory infection of viruses (e.g., influenza virus) remain a significant challenge due to lack of effective antiviral therapy. These viruses primarily infect human airway epithelium. The mechanisms underlying viral infection, tissue injury and inflammation have not been well understood. In this project, we will focus on the role of a multifunctional immune regulator Toll- interacting protein (Tollip) in viral infection, particularly influenza A virus (IAV) as it represents a more severe form of viral infection in asthma. One of the key cytokines involved in asthma pathogenesis is IL-33, which is expressed by airway epithelial cells and other structural cells, and can be released during tissue injury following viral infection. Through binding to membrane-bound receptor ST2L, IL-33 exerts a variety of functions involved in asthma pathogenesis. By using a Tollip knockout mouse model of IAV infection, we discovered that Tollip deficiency increased lung viral load, loss of body weight, airway neutrophilic inflammation and importantly the release of cleaved IL-33 into the airway lumen. Mechanistically, Tollip deficiency delayed airway epithelial wound healing, reduced the production of IL-33 decoy receptor soluble ST2 (sST2), and increased mucous goblet cells expressing ST2L in IL-13-stimulated airway epithelial cells. We hereby hypothesize that Tollip is protective against viral exacerbations of asthma by inhibiting the IL-33 signaling. In Aim 1, we will define the role of Tollip in IL-33 release and activation during viral infection in airways with type 2 inflammation by testing if Tollip is protective against airway epithelial injury by promoting epithelial wound healing and reducing ATP release during respiratory viral infection in human airway epithelial cells and mouse models with type 2 inflammation. In Aim 2, we will determine sST2 regulation by Tollip during viral infection in airways with type 2 inflammation by testing if Tollip increases transcriptional activity of the ST2 proximal promoter to induce sST2 expression in part through inhibiting activation of STAT3. In Aim 3, we will determine ST2L regulation by Tollip during viral infection in airways with type 2 inflammation by testing if Tollip inhibits ST2L expression by reducing mucous goblet cells in airway epithelial cells exposed to IL-13/IL-33 and IAV. The proposed studies in Project 2 will reveal novel mechanisms by which Tollip deficiency due to genetic and/or environmental factors promotes airway injury and inflammation in a type 2 inflammation setting. sST2 or agents to reduce released ATP function/activity may serve as a therapy to correct the detrimental effect of Tollip deficiency-mediated IL-33 signaling in airways during viral exacerbations of asthma.