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

基本信息

批准号：
10514569
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
项目类别：
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/10514569
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 Macrophage 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 neutrophil new therapeutic target novel peripheral blood receptor response targeted treatment therapeutic target transcriptome sequencing translational impact

项目摘要

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.

拟议的研究的目的是确定调节嗜中性肺的机制新型严重哮喘中的炎症和气道高反应性（AHR）。新的治疗靶标非型2或中性粒细胞严重哮喘需要至关重要的。白介素33（IL-33）驱动器2 先天淋巴样细胞（ILC2S）促进2型嗜酸性肺炎症，但有新兴的证据表明存在明显的ILC2可塑性，可以使表型切换至第1组ILC（ILC1）促进1型炎症。我们已经开发了一种新颖的先天严重哮喘模型中性粒细胞炎症，高皮质类固醇耐药性AHR，ILC2至ILC1偏移以及1型升高和升高 2个干扰素水平。我们假设干扰素基因（Sting）的刺激器调节模型中的炎症和AHR反应以及将ILC可塑性驱动到ILC1表型中。我们将确定刺激在AHR和中性粒细胞炎症中的作用敲除小鼠以及接收sting拮抗剂的野生型小鼠。此外，我们将评估共同封锁Sting和IL-33作为模型中的治疗策略，并使用收养转移研究来研究ILC2的可塑性和ILC在严重哮喘模型表型中的作用。我们也会确定刺激的细胞来源，包括来自ILC表达的潜在新贡献蜇。此外，我们将评估1型和/或2型干扰素受体和STAT1是否是模型中严重哮喘的特征所需。最后，我们将使用人类肺和外周血样本以确定刺激在ILC可塑性中的翻译影响并评估表达水平来自哮喘和对照的样品中与STING相关的途径转录本的。因为新的治疗是在退伍军人中，严重的非型2哮喘需要，这些研究支持刺痛作为潜在的候选者在严重哮喘中驱动中性粒细胞性肺部炎症和气道高反应性时。