Genetic and Epigenetic Programming of Allergic Airway Inflamation

哮喘发展和严重程度的一个重要因素是暴露于空气中的颗粒物和污染物。 由车辆交通排放的颗粒物（PM）由于其引发哮喘而对哮喘尤其有害。 气道和全身炎症及其促变应性佐剂功能。我们最近发现 Notch通路是PM加重气道炎症的关键机制。PM诱导 Notch配体Jagged 1（Jag 1）在抗原呈递细胞（APC）中，最明显的是CD 11 chigh肺巨噬细胞， 芳香烃受体依赖性机制。肺巨噬细胞中Jagged 1诱导的抑制 消除PM的促过敏性炎症作用。重要的是，PM促进气道炎症， 与人促哮喘IL-4受体α链（IL-4 R α）变体IL-4 R α-R576的相互作用， 最近发现通过使变应原特异性诱导的（i）- Treg细胞转化为Th 17细胞样细胞。我们还确定了Treg细胞中的Notch信号负性 影响其调节功能。Treg细胞特异性抑制Notch信号传导有效抑制过敏性 气道炎症及其由PM引起的恶化，表明Treg细胞中的Notch信号传导是一个共同的目的， 在过敏性气道炎症中的作用机制，可能与IL-4 R α-R576协同进行。 关于由过敏原和PM激活的Notch途径，包括 Notch受体及其下游经典和非经典信号传导途径的特性 涉案也相关的是其他细胞基质参与，包括APC和先天淋巴细胞2型 （国际法委员会第2条）。阐明PM与IL-4 R α-R576在促进哮喘发病率和严重程度方面的相互作用， 人类受试者与治疗和预防特别相关。因此，我们的中心假设是， PM通过激活涉及APC、ILC 2的Jagged 1-Notch信号通路促进过敏性气道炎症 尤其是Treg细胞。我们还提出，选择性Notch受体，最明显的是Notch 4， Notch 3在这一过程中起着至关重要的作用，PM炎症的关键机制是 通过单独和与IL-4 R α-R576协同作用使过敏原特异性Treg细胞失稳。最后，我们建议 利用现有的哮喘队列研究通过Notch途径起作用的PM与IL-4 R α- R576等位基因在哮喘Th 2/Th 17混合细胞炎症中的作用 诱导Treg细胞形成致病性Th 17细胞。我们还将受试者PM暴露与IL 4 R576 等位基因携带与哮喘症状和炎症的严重程度相关。我们的研究将有助于阐明 过敏性气道炎症的生物学基础机制及其由PM引起的增强，以及 阐明了新的致病途径，可以在哮喘受试者的治疗靶向。

An important contributor to asthma development and severity is exposure to airborne particles and pollutants. Particulate matter (PM) emitted by vehicular traffic is especially harmful in asthma by virtue of its initiation of airway and systemic inflammation and its pro-allergic adjuvant function. We have recently identified activation of the Notch pathway as a key mechanism by which PM exacerbate airway inflammation. PM induces the Notch ligand Jagged 1 (Jag1) in antigen presenting cells (APC), most notably CD11chigh lung macrophages, by an aryl hydrocarbon receptor-dependent mechanism. Inhibition of Jagged 1 induction in lung macrophages abrogates the pro-allergic inflammatory effects of PM. Importantly, PM promote airway inflammation in interaction with the human pro-asthmatic IL-4 receptor alpha chain (IL-4Rα) variant IL-4Rα-R576, which we recently found to promote dual Th2/Th17 airway inflammation by destabilizing allergen-specific induced (i)- Treg cells into Th17 cell like cells. We have also established that Notch signaling in Treg cells negatively affects their regulatory function. Treg cell-specific inhibition of Notch signaling potently suppresses allergic airway inflammation and its exacerbation by PM, indicating that Notch signaling in Treg cells is a common end mechanism in allergic airway inflammation, which may proceed in synergy with IL-4Rα-R576. Fundamental questions remain regarding the Notch pathways activated by allergens and PM, including the identity of the Notch receptor(s) and their downstream canonical and non-canonical signaling pathways involved. Also relevant are other cellular substrates involved, including APCs and innate lymphoid cells type 2 (ILC2). Elucidating the interaction of PM with IL-4Rα-R576 in promoting asthma morbidity and severity in human subjects is of particular relevance to therapy and prevention. Accordingly, our central hypothesis is that PM promotes allergic airway inflammation by activating a Jagged1-Notch signaling circuit involving APC, ILC2 and particularly Treg cells. We also propose that selective Notch receptors, most notably Notch4 and possibly Notch3, play a cardinal role in this process, and that a key mechanism by which PM worsens inflammation is by destabilizing allergen-specific Treg cells alone and in synergy with IL-4Rα-R576. Finally, we propose to leverage existing asthma cohorts to study the interaction of PM, acting via the Notch pathway, and the IL-4Rα- R576 allele in driving mixed Th2/Th17 cell inflammation in asthma by promoting the subversion of newly formed induced Treg cells into pathogenic Th17 cells. We will also relate subject PM exposure and IL4R576 allele carriage to the severity of asthmatic symptoms and inflammation. Our studies will help elucidate novel mechanisms fundamental to the biology of allergic airway inflammation and its augmentation by PM, and illuminate novel pathogenic pathways that could be therapeutically targeted in asthmatic subjects.