Roles of STING and innate lymphoid cell plasticity in severe asthma

STING 和先天淋巴细胞可塑性在严重哮喘中的作用

• 批准号: 10293537
• 负责人: TAYLOR A DOHERTY
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293537
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Adrenal Cortex Hormones; Agonist; Allergens; Allergic; Alternaria; Asthma; Automobile Driving; Blood specimen; Bone Marrow; CD4 Positive T Lymphocytes; Cell secretion; Cells; Chimera organism; Cost of Illness; Cytoplasmic Protein; Data; Detection; Disease; Donor person; Epithelial Cells; Exposure to; Gene Expression; Goals; Health Care Costs; Helper-Inducer T-Lymphocyte; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferon Receptor; Interferon Type II; Interferons; Interleukin-5; Interleukins; Knockout Mice; Leukocytes; Lung; Lymphocyte; Lymphoid Cell; Middle East; Military Personnel; Modeling; Morbidity - disease rate; Mucous body substance; Mus; Myelogenous; Neutrophilia; Pathway interactions; Periodicity; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Prevalence; Production; Protocols documentation; Pulmonary Inflammation; Reporting; Research; Resistance; Role; STAT1 gene; Sampling; Second Messenger Systems; Signal Transduction; Source; Stimulator of Interferon Genes; T-Lymphocyte Subsets; Therapeutic; Transcript; Veterans; Wild Type Mouse; airway hyperresponsiveness; airway inflammation; antagonist; asthma model; asthmatic; asthmatic patient; cell type; cytokine; eosinophil; experimental study; gene function; in vivo; inhibitor; macrophage; neutrophil; new therapeutic target; novel; peripheral blood; receptor; response; targeted treatment; therapeutic target; transcriptome sequencing; translational impact

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.

这项研究的目的是确定调节嗜肺细胞的机制， 炎症和气道高反应性（AHR）在一个新的严重哮喘。新的治疗靶点 对于非2型或嗜中性粒细胞的严重哮喘是非常需要的。白细胞介素-33（IL-33）驱动第2组 先天性淋巴样细胞（ILC 2）促进2型嗜酸性粒细胞肺炎，但新出现的证据 表明存在显著的ILC 2可塑性，允许表型转换为第1组ILCs（ILC 1） 促进1型炎症。我们开发了一种新的先天性重度哮喘模型， 嗜酸性炎症、高皮质类固醇耐药AHR、ILC 2向ILC 1转变以及1型和 2干扰素水平。我们假设干扰素基因刺激因子（STING）调节了 炎症和AHR反应以及驱动ILC可塑性朝向ILC 1表型。 我们将确定野生型和STING中STING在AHR和嗜酸性炎症中的作用。 敲除小鼠以及接受STING拮抗剂的野生型小鼠。此外，我们将评估共同- 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ILC 2可塑性和ILCs在严重哮喘模型表型中的作用。我们还将 确定STING的细胞来源，包括来自ILC表达的潜在新贡献， 刺痛。此外，我们还将评估1型和/或2型干扰素受体和STAT 1是否在 模型中严重哮喘的特征所需。最后，我们将使用人的肺和外周血 样品以确定STING在ILC可塑性中的翻译影响并评估表达水平 STING相关通路转录物在哮喘患者和对照组样本中的表达。因为新的治疗方法 这些研究支持STING作为潜在的候选药物， 导致严重哮喘患者的嗜酸性肺部炎症和气道高反应性。