Der p 2-driven TLR4 signaling in allergic asthma

过敏性哮喘中 Der p 2 驱动的 TLR4 信号传导

• 批准号: 8543491
• 负责人: Jaclyn W McAlees
• 金额: $ 1.39万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543491
• 关键词: Adjuvant; Allergens; Antigen-Presenting Cells; Automobile Driving; Binding; Biological; Cell Line; Cell surface; Cells; Chronic; Chronic lung disease; Complex; Data; Dendritic Cells; Dermatophagoides pteronyssinus antigen p 2; Development; Endosomes; Epithelial Cells; Experimental Models; Extrinsic asthma; Genetic; Goals; House Dust Mite Allergens; IRF3 gene; Immune response; Immune system; Inflammation; Inflammatory; Interferons; Laboratories; Lung diseases; Measures; Mediating; Mediator of activation protein; Molecular; Molecular Mimicry; Mus; Myeloid Cells; Pathway interactions; Phase; Prevalence; Preventive; Production; Proteins; Recruitment Activity; Respiratory physiology; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; TLR4 gene; Therapeutic; Transgenic Mice; Work; activating transcription factor; allergic airway inflammation; base; chemokine; cytokine; in vivo; mouse model; reconstitution; research study; response

DESCRIPTION (provided by applicant): Allergic asthma is thought to result from Th2-polarized immune responses to otherwise apparently innocuous environmental proteins. Why specific proteins drive such maladaptive immune responses in susceptible hosts has been unclear. Our lab and others have suggested that direct, (dys)functional interactions between such proteins and the innate immune system are central to the molecular basis of allergenicity. In the case of Der p 2, a major house dust mite allergen, our data indicate that it tends to be a target of adaptive immune responses because it has intrinsic adjuvant activity due to its molecular mimicry of MD-2, the LPS-binding subunit of the TLR4 complex. Der p 2 can reconstitute and augment TLR4 signaling in the absence and presence of MD-2, respectively. In addition, Der p 2 drives TLR4-dependent, MD- 2-independent Th2-polarized inflammation in the airways of mice. Recent data suggest that the relevant locus of TLR4 signaling important for driving Th2 inflammation in the airway involves TLR4 signaling by airway epithelial cells (AECs), which regulate the development of aeroallergic responses via the production of chemokines and cytokines that recruit and regulate the function of lung dendritic cells. MD-2-dependent TLR4 signaling involves activation of both Mal/MyD88 and TRIF/TRAM pathways of signal transduction. The molecular mechanisms underlying Der p 2-dependent TLR4 signaling remain to be defined. Based on preliminary data, we hypothesize that: (a) like MD-2, Der p 2 drives TLR4 signaling via both pathways; but (b) the allergenicity of Der p 2 is depends primarily on TRIF/TRAM signaling. The proposed experiments will define the signaling pathways activated by Der p 2-dependent TLR4 stimulation in genetically tractable cell lines; determine the Th2-polarizing cellular responses (and underlying signaling pathways) driven by Der p 2-driven TLR4 signaling in primary AECs; and define the TLR4-driven signaling pathways essential to the in vivo allergenicity of Der p 2 using genetic mouse models. The long-term goal of this proposal is to define the signaling pathways activated by Der p 2 and their biological consequences for aeroallergy, in order to devise new preventive and/or therapeutic strategies for allergic asthma.

描述（由申请人提供）：过敏性哮喘被认为是由对原本看似无害的环境蛋白质的 Th2 极化免疫反应引起的。为什么特定蛋白质会在易感宿主中驱动这种适应不良的免疫反应，目前尚不清楚。我们的实验室和其他实验室表明，此类蛋白质与先天免疫系统之间直接的（功能失调）相互作用是过敏性分子基础的核心。就 Der p 2（一种主要的屋尘螨过敏原）而言，我们的数据表明它往往是适应性免疫反应的目标，因为它具有内在的佐剂活性，因为它具有 MD-2（TLR4 复合物的 LPS 结合亚基）的分子模拟。 Der p 2 可以分别在不存在和存在 MD-2 的情况下重建和增强 TLR4 信号传导。此外，Der p 2 在小鼠气道中驱动 TLR4 依赖性、MD-2 独立的 Th2 极化炎症。最近的数据表明，TLR4 信号传导的相关位点对于驱动气道 Th2 炎症非常重要，涉及气道上皮细胞 (AEC) 的 TLR4 信号传导，AEC 通过产生趋化因子和细胞因子来招募和调节肺树突状细胞的功能，从而调节空气过敏反应的发展。 MD-2 依赖性 TLR4 信号传导涉及 Mal/MyD88 和 TRIF/TRAM 信号转导途径的激活。 Der p 2 依赖性 TLR4 信号传导的分子机制仍有待确定。根据初步数据，我们假设：(a) 与 MD-2 一样，Der p 2 通过两条途径驱动 TLR4 信号传导；但 (b) Der p 2 的过敏性主要取决于 TRIF/TRAM 信号传导。拟议的实验将定义在遗传易处理细胞系中由 Der p 2 依赖性 TLR4 刺激激活的信号通路；确定原代 AEC 中由 Der p 2 驱动的 TLR4 信号传导驱动的 Th2 极化细胞反应（和潜在的信号传导途径）；并使用遗传小鼠模型定义了对 Der p 2 体内过敏性至关重要的 TLR4 驱动信号通路。该提案的长期目标是确定 Der p 2 激活的信号通路及其对空气过敏的生物学影响，以便为过敏性哮喘设计新的预防和/或治疗策略。