Genetic and Epigenetic Programming of Allergic Airway Inflamation

导致哮喘发展和严重程度的一个重要因素是暴露在空气中的颗粒物和污染物。 车辆排放的颗粒物(PM)对哮喘的危害尤其严重，因为它会引发 呼吸道和全身炎症及其促过敏佐剂功能。我们最近发现了激活 Notch通路是PM加重呼吸道炎症的关键机制。PM诱导了 抗原提呈细胞(APC)中的缺口配体Jag1(Jag1)，尤其是CD11肺巨噬细胞，通过 芳香烃受体依赖的机制。Jagge1对肺巨噬细胞诱导的抑制作用 消除PM的促过敏性炎症作用重要的是，PM促进了呼吸道炎症 与人哮喘前期IL-4受体阿尔法链(IL-4Rα)变异体IL-4Rα-R576的相互作用 最近发现通过破坏变应原诱导的双Th2/Th17气道炎症(I)- Treg细胞分化为Th17细胞样细胞。我们还证实了Treg细胞中的Notch信号是负性的 会影响它们的调节功能。Treg细胞特异性抑制Notch信号可有效抑制过敏反应 呼吸道炎症及其PM的加重，表明Treg细胞中的Notch信号是共同的结果 过敏性呼吸道炎症的机制，可能与IL-4Rα-R576协同进行。 关于由过敏原和PM激活的Notch通路，基本问题仍然存在，包括 Notch受体(S)及其下游典型和非典型信号通路的识别 牵涉其中。与此相关的还有其他细胞底物，包括APC和2型先天淋巴细胞。 (ILC2)。PM与IL-4R、α-R576在促进哮喘发病率和严重程度中的相互作用 人体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、ILC2的Jagged1-Notch信号通路促进过敏性呼吸道炎症 尤其是Treg细胞。我们还提出选择性Notch受体，最显著的是Notch4和可能的 NOTCH3在这一过程中发挥了关键作用，PM加重炎症的一个关键机制是 通过单独以及与IL-4Rα-R576协同破坏过敏原特异性Treg细胞的稳定。最后，我们建议 利用现有哮喘队列研究PM的相互作用，通过Notch途径发挥作用，以及IL-4Rα- R576等位基因在哮喘Th2/Th17混合性细胞炎症中的作用 将诱导的Treg细胞转化为致病Th17细胞。我们还将把PM暴露和IL4R576联系起来 等位基因携带与哮喘症状和炎症的严重程度有关。我们的研究将有助于阐明小说 过敏性呼吸道炎症生物学的基本机制以及PM对其的增强作用 阐明可用于治疗哮喘受试者的新致病途径。

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.