Roles of STING and innate lymphoid cell plasticity in severe asthma

这项拟议的研究的目标是确定调节中性粒细胞肺的机制。 一种新的重症哮喘患者的炎症和气道高反应性。新的治疗靶点 对于非2型或中性粒细胞严重哮喘来说是非常需要的。白介素33(IL-33)驱动第二组 先天淋巴样细胞(ILC2s)促进2型嗜酸性肺炎，但新的证据 提示存在显著的ILC2可塑性，允许将表型转换为组1 ILC(ILC1s) 促进1型炎症的物质。我们已经开发出一种新的先天重度哮喘模型 中性粒细胞炎症，对糖皮质激素高度耐药的AHR，ILC2到ILC1的转变，以及1型和 2干扰素水平。我们假设干扰素基因刺激物(STIN)调节 模型中的炎症和AHR反应以及推动ILC向ILC1表型的可塑性。 我们将确定刺痛在AHR和野生型和刺痛的中性粒细胞炎症中的作用 基因敲除小鼠以及接受刺痛拮抗剂的野生型小鼠。此外，我们将评估联合- 阻断STING和IL-33作为模型中的治疗策略，并使用过继转移研究 研究ILC2的可塑性及其在重症哮喘模型表型中的作用。我们还将 确定STIN的细胞来源，包括ILC表达的潜在新贡献 刺痛。此外，我们将评估1型和/或2型干扰素受体和STAT1是否 模型中严重哮喘的特征所必需的。最后，我们将使用人的肺和外周血液 样本以确定STING在ILC可塑性中的翻译影响并评估表达水平 哮喘患者和对照组样本中刺痛相关途径转录本的研究。因为新的治疗方法是 退伍军人严重的非2型哮喘所需，这些研究支持将斯汀作为一个潜在的候选 在推动严重哮喘的中性粒细胞肺部炎症和呼吸道高反应性方面。

The goal of the proposed research is to identify mechanisms that regulate neutrophilic lung inflammation and airway hyperresponsiveness (AHR) in a novel severe asthma. New therapeutic targets are critically needed for non-type 2 or neutrophilic severe asthma. Interleukin-33 (IL-33) drives group 2 innate lymphoid cells (ILC2s) to promote type 2 eosinophilic lung inflammation, but emerging evidence suggests that significant ILC2 plasticity exists that allows a switch in phenotype to group 1 ILCs (ILC1s) that promote type 1 inflammation. We have developed a novel innate severe asthma model with neutrophilic inflammation, high corticosteroid-resistant AHR, ILC2 to ILC1 shift ,and elevated type 1 and 2 interferon levels. We hypothesize that stimulator of interferon genes (STING) regulates the inflammatory and AHR responses in the model as well as drives ILC plasticity towards an ILC1 phenotype. We will determine the role of STING in AHR and neutrophilic inflammation in wild type and STING knockout mice as well as in wild type mice receiving STING antagonists. Further, we will assess co- blockade of STING and IL-33 as a therapeutic strategy in the model and use adoptive transfer studies to investigate ILC2 plasticity and the role of ILCs in the severe asthma model phenotype. We will also identify the cellular sources of STING, including potential novel contributions from ILC expression of STING. Additionally, we will assess whether type 1 and/or type 2 interferon receptors and STAT1 are required for features of severe asthma in the model. Finally, we will use human lung and peripheral blood samples to determine the translational impact of STING in ILC plasticity and evaluate expression levels of STING-related pathway transcripts in samples from asthmatics and controls. As novel treatments are needed for severe non-type 2 asthma in Veterans, these studies support STING as a potential candidate in driving neutrophilic lung inflammation and airway hyperresponsiveness in a severe asthma.