Mechanisms of IL-17A-mediated enhancement of asthma severity

IL-17A 介导的哮喘严重程度增强的机制

• 批准号: 8670181
• 负责人: Ian Paul Lewkowich
• 金额: $ 37.88万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670181
• 关键词: Accounting; Activating Transcription Factor 2; Acute; Address; Adrenal Cortex Hormones; Allergens; Animal Model; Animals; Asthma; Automobile Driving; Binding; CCAAT-Enhancer-Binding Proteins; Case-Control Studies; Cells; Cessation of life; Child; Childhood; Childhood Asthma; Chronic; Clinical; Complex; Data; Development; Disease; Dissociation; Elements; Environmental Exposure; Epidemiology; Epithelial Cells; Exposure to; Extrinsic asthma; Gene Expression; Genes; Genetic Transcription; Goals; Hereditary Disease; Hospitalization; Human; Human Cell Line; Immune response; In Vitro; Incidence; Indium; Individual; Inflammatory; Interleukin-13; Interleukin-17; Knowledge; Lead; Link; Lung diseases; Mediating; Minority Groups; Molecular; Monitor; Morbidity - disease rate; Mus; Mutate; NF-kappa B; Nose; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Play; Population; Process; Production; Refractory; Resistance; Resources; Risk; STAT6 gene; Serum; Severities; Severity of illness; Signal Transduction; TNF receptor-associated factor 3; Target Populations; Testing; Therapeutic Intervention; Translating; Translational Research; Underserved Population; activating transcription factor; airway hyperresponsiveness; clinical infrastructure; cytokine; design; experience; health disparity; in vivo; interleukin-13 receptor; low socioeconomic status; mortality; mouse model; novel; novel therapeutics; operation; prevent; promoter; public health relevance; receptor; repository; response; therapeutic target

DESCRIPTION (provided by applicant): Asthma is a chronic, inflammatory disease of the lung that currently afflicts more than 300 million people worldwide. While asthma is mediated by an excessive Th2 immune response to allergens, recent evidence suggests that production of the Th17 cytokine, IL-17A, is associated with the development of more severe disease. While severe asthmatics are at greatest risk for morbidity or death following acute exacerbations, and can be refractory to therapies that are highly effective in individuals with mild disease, the molecular mechanisms whereby IL-17A contributes to the development of severe allergic asthma are ill-defined. A greater understanding of the molecular mechanisms through which IL-17A facilitates severe asthma would provide additional therapeutic targets for populations underserved by current therapies. Using a mouse model we provide evidence that severe asthma is associated with increased IL-17A production, and is compounded by enhanced Il17ra expression and elevated responsiveness to IL-17A. These alterations in IL-17A production and responsiveness exacerbate IL-13-driven STAT6 activation, gene expression, and airway responses. Our preliminary data suggests that IL-17A-mediated enhancement of IL-13-driven responses occur through two, non-mutually independent mechanisms in mouse cells; 1) by causing the dissociation of a complex including IL-13R¿1 and TRAF3, which normally limits IL-13-driven STAT6 phosphorylation, and 2) by activating transcription factors (NF-¿B, C/EBP¿ and C/EBP¿) which can enhance IL-13/STAT6 driven gene expression. While preliminary studies presented here also suggest that similar mechanisms may operate in human cell lines, the extent to which the observations made in our mouse model apply to humans with severe asthma is unclear. Three specific aims are proposed to identify the molecular mechanisms through which IL-17A enhances asthma severity in mice, and humans. Specific Aim 1 will determine if the increased IL-13-driven STAT6 phosphorylation and AHR observed in the presence of IL-17A is the result of the dissociation of the IL- 13R¿1:TRAF3 complex following initiation of IL-17A signaling. Specific Aim 2 will dissect the importance of IL- 17A-driven activation of NF-¿B (canonical versus non-canonical), C/EBP¿ and C/EBP¿ in IL-13/IL-17A synergy in vitro and in vivo. Specific Aim 3 will directly test whether similar synergistic interactions between IL-13 and IL-17A are observed in asthma relevant, primary human cells. Additionally, we will determine whether severe asthma in children is associated, as it is in the mouse, with increased IL-17A production, IL17RA expression, and IL-17A responsiveness. Collectively, the studies proposed in this application will move us beyond the "Th2 paradigm" of allergic asthma, begin to characterize the mechanisms whereby Th17-products trigger the development of severe allergic asthma, and determine whether similar mechanisms may be at play in mice and humans. A better understanding of these mechanisms will enable us to identify novel targets for therapeutic interventions in individuals with severe asthma, a population underserved by current therapies.

描述（由适用提供）：哮喘是一种肺部的慢性炎症性疾病，目前遭受了全球超过3亿人的折磨。尽管哮喘是由过量的TH2免疫响应对过敏原介导的，但最近的证据表明，Th17细胞因子IL-17A的产生与更严重的疾病的发展有关。尽管严重的哮喘患者在急性加重后有发病率或死亡的危险，并且可能对在轻度疾病患者中非常有效的疗法难治性，但分子机制有助于IL-17A有助于严重过敏性哮喘的发展。对IL-17A促进严重哮喘的分子机制有更深入的了解将为当前疗法服务不足的种群提供额外的治疗靶标。使用小鼠模型，我们提供了证据表明严重的哮喘与IL-17A产生增加有关，并通过增强的IL17RA表达和对IL-17A的反应性提高而加剧。 IL-17A的产生和响应性中的这些改变加剧了IL-13驱动的STAT6激活，基因表达和气道响应。我们的初步数据表明，IL-17A介导的IL-13驱动响应的增强是通过小鼠细胞中的两种非多独立的机制发生的。 1）通过引起包括IL-13R¿1和TRAF3在内的复合物的解离，这通常限制IL-13驱动的STAT6磷酸化，以及2）通过激活转录因子（NF-€，C/C/EBP？和C/EBP）来增强IL-13/Stat6驱动基因表达。虽然这里介绍的初步研究也表明类似的机制可能在人类细胞系中起作用，但我们的小鼠模型中对患有严重哮喘的人类进行的观察结果的程度尚不清楚。提出了三个特定的目的，以确定IL-17A增强小鼠和人类哮喘严重程度的分子机制。具体的目标1将确定在IL-17a存在下观察到的IL-13驱动的STAT6光态和AHR是否是IL-13R¿1：TRAF3复合物在IL-17A信号传导之后解离的结果。具体目标2将阐述IL-17a驱动的NF-€B（规范与非典型的），C/EBP¿和C/EBP¿在IL-13/IL-17A在体外和体内的协同作用中的重要性。具体目标3将直接测试在哮喘相关的原代人细胞中是否观察到IL-13和IL-17a之间的类似协同相互作用。此外，我们将确定儿童的严重哮喘是否像小鼠中一样与IL-17A产生，IL17RA表达和IL-17A反应性增加相关。总的来说，本应用中提出的研究将使我们超越过敏性哮喘的“ Th2范式”，开始表征Th17产物触发严重过敏性哮喘的发展的机制，并确定在小鼠和人类中是否可能在作用类似的机制。对这些机制的更好理解将使我们能够确定严重哮喘患者热干预措施的新颖靶标，这是当前疗法的人群。