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: 9234041
• 负责人: Ian Paul Lewkowich
• 金额: $ 39万
• 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/9234041
• 关键词: 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; Hospitalization; Human; Human Cell Line; Immune response; In Vitro; Incidence; 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; Recruitment Activity; Refractory; Resistance; Resources; Risk; STAT6 gene; Serum; Severities; Severity of illness; Signal Transduction; TNF receptor-associated factor 3; 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; new therapeutic target; novel; novel therapeutics; operation; prevent; promoter; public health relevance; receptor; repository; response; synergism; 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，目前全世界有超过 3 亿人患有哮喘。虽然哮喘是由对过敏原的过度 Th2 免疫反应介导的，但最近的证据表明，Th17 细胞因子的产生， IL-17A 与更严重疾病的发展相关，而严重哮喘患者在急性发作后发病或死亡的风险最大，并且可能难以治疗。虽然 IL-17A 对患有轻度疾病的个体非常有效，但 IL-17A 导致严重过敏性哮喘发展的分子机制尚不明确。更好地了解 IL-17A 促进严重哮喘的分子机制将提供额外的治疗靶点。对于目前治疗不足的人群，我们提供了证据表明严重哮喘与 IL-17A 产生增加有关，并且 IL-17ra 表达增强和对 IL-17A 产生的反应性升高加剧了这些变化。我们的初步数据表明，IL-17A 介导的 IL-13 驱动反应的增强是通过小鼠细胞中两种非相互独立的机制发生的。 ) 通过引起包括 IL-13R�1 和 TRAF3 在内的复合物解离，该复合物通常限制 IL-13 驱动的 STAT6 磷酸化，以及 2) 通过激活转录因子（NF-�B、 C/EBP� 和 C/EBP�) 可以增强 IL-13/STAT6 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发挥作用，但在我们的小鼠模型中观察到的程度。提出了三个具体目标来确定 IL-17A 增强小鼠哮喘严重程度的分子机制，而具体目标 1 将确定 IL-13 驱动的 STAT6 磷酸化和 AHR 是否增加。观察到IL-17A 的存在是 IL-17A 信号传导启动后 IL-13R�1:TRAF3 复合物解离的结果。具体目标 2 将剖析 IL-17A 驱动的 NF-�B 激活的重要性。规范与非规范），C/EBP® 和 C/EBP® 在体外和体内 IL-13/IL-17A 协同作用中将直接发挥作用。测试是否在哮喘相关的原代人类细胞中观察到 IL-13 和 IL-17A 之间类似的协同相互作用。此外，我们将确定儿童的严重哮喘是否与小鼠中的 IL-17A 产量增加相关。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“Th2范式”，开始表征Th17产物引发严重过敏性哮喘的机制，并确定。类似的机制是否可能在小鼠和人类中发挥作用，更好地了解这些机制将使我们能够确定对患有严重哮喘的个体进行治疗干预的新靶点，而该人群目前的治疗方法还不够。