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: 8842705
• 负责人: Ian Paul Lewkowich
• 金额: $ 37.31万
• 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/8842705
• 关键词: ATF2 gene; Accounting; 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; Health; Hereditary Disease; Hospitalization; Human; Human Cell Line; Immune response; In Vitro; Incidence; Indium; Individual; Interleukin-13; Interleukin-17; Knowledge; Lead; Link; 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; asthmatic; clinical infrastructure; cytokine; design; experience; health disparity; in vivo; inflammatory lung disease; interleukin-13 receptor; low socioeconomic status; mortality; mouse model; novel; novel therapeutics; operation; prevent; promoter; 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（由申请人提供）：哮喘是一种慢性炎症性肺部疾病，目前困扰着全球3亿多人。虽然哮喘是由对过敏原的过度Th 2免疫应答介导的，但最近的证据表明，Th 17细胞因子IL-17 A的产生与更严重疾病的发展相关。虽然重度哮喘患者在急性加重后发病或死亡的风险最大，并且可能对轻度疾病个体中高度有效的治疗无效，但IL-17 A导致重度过敏性哮喘发展的分子机制尚不明确。更深入地了解IL-17 A促进重度哮喘的分子机制将为目前治疗不足的人群提供额外的治疗靶点。使用小鼠模型，我们提供的证据表明，严重哮喘与IL-17 A的产生增加，并通过增强的IL-17 ra表达和对IL-17 A的反应性升高而复合。IL-17 A产生和反应性的这些改变加剧了IL-13驱动的STAT 6活化、基因表达和气道反应。我们的初步数据表明，在小鼠细胞中，IL-17 A介导的IL-13驱动反应的增强通过两种非相互独立的机制发生：1）通过引起包括IL-13 R 1和TRAF 3的复合物的解离，其通常限制IL-13驱动的STAT 6磷酸化，和2）通过激活转录因子（NF-B、C/EBP和C/EBP），其可以增强IL-13/STAT 6驱动的基因表达。虽然本文提出的初步研究也表明，类似的机制可能在人类细胞系中起作用，但在我们的小鼠模型中观察到的结果在多大程度上适用于患有严重哮喘的人类尚不清楚。提出了三个具体目标，以确定IL-17 A增强小鼠和人类哮喘严重程度的分子机制。特异性目的1将确定在IL-17 A存在下观察到的IL-13驱动的STAT 6磷酸化和AHR增加是否是IL-17 A信号传导启动后IL-13 R1：TRAF 3复合物解离的结果。具体目标2将剖析IL-17 A驱动的NF-B（规范与非规范）、C/EBP和C/EBP活化在IL-13/IL-17 A体外和体内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-17 A之间的类似协同相互作用。此外，我们将确定儿童重度哮喘是否与小鼠中IL-17 A产生、IL-17 RA表达和IL-17 A反应性增加相关。总的来说，本申请中提出的研究将使我们超越过敏性哮喘的“Th 2范例”，开始表征Th 17产物触发严重过敏性哮喘发展的机制，并确定在小鼠和人类中是否存在类似的机制。更好地了解这些机制将使我们能够确定新的目标，为治疗干预的个人与严重哮喘，人口不足，目前的治疗。