PGI2 inhibition of pulmonary innate allergic immune responses

过敏性呼吸道炎症是哮喘的一个特征，哮喘是美国最常见的慢性疾病之一 各州。第二组先天淋巴样细胞(ILC2)是最近被描述的一种细胞类型，其产生能力要强得多 IL-5和IL-13在每个细胞的基础上比CD4+Th2细胞更重要，而且越来越多的证据表明ILC2是至关重要的 与变态反应性炎症反应的发生和放大有关。在此退伍军人奖励计划的上一个资助周期中 ，我们报道了前列腺素(PG)I2在体外和体内对ILC2功能的负面调节，而 抑制先天免疫介导的呼吸道嗜酸性粒细胞增多症、粘液化生和呼吸道反应性， 哮喘表型的基本特征。我们新的体内初步数据有力地表明，PGI2 信号转导抑制Alt Ex诱导的气道释放IL-33，IL-33是一种与ST2受体结合的警报细胞因子 ILC2和其他细胞。多基因组范围关联研究(GWAS)已确定IL-33和ST2为 哮喘易感基因。这一应用中的实验具有重要的临床意义，因为NIH- 资助的重症哮喘研究项目(SARP)报告称，PGI2受体(简称PGI2受体)的基因表达 PTGIR)是最能区分重症哮喘患者和其他患者的基因之一。 有轻微疾病和健康对照。在SARP中，重度哮喘患者的病情显著降低，但不是 缺失)基因表达的PGI2受体。此应用程序的长期目标是确定 上皮中PGI2受体表达降低与重度哮喘相关的机制 (目标1)并确定内源性PGI2信号和外源性PGI2抑制的分子机制 ILC2的增殖和功能(目标2)。研究内源性PGI2的作用对于理解 应用最广泛的非处方药之一--环氧合酶抑制药的疗效 在世界上，由于这些药物抑制PGI2的产生，对先天过敏免疫反应。调查 外源性PGI2的作用对于了解吸入PGI2或其类似物对 先天过敏免疫反应，因为这类药物是FDA批准的，目前用于治疗 因此，它的使用可用于治疗过敏性呼吸道疾病，如 作为哮喘。这些研究正在转变范式，因为目前没有已知的FDA批准的阴性 空气变应原诱导IL-33释放的调节剂，我们的初步数据有力地支持PGI2可能是 第一个描述。研究内源性前列腺素I2的作用对于理解内源性前列腺素I2的作用至关重要 环氧合酶抑制药是世界上应用最广泛的非处方药之一 世界上，由于这些药物抑制PGI2的产生，这些药物对先天过敏免疫反应的影响。建议数 实验将推动这一领域的发展，因为它们将定义PGI2，一种FDA批准的目前用于 肺动脉高压，控制早期的先天过敏免疫反应。PGI2目前可用于 人类治疗突出了我们应用的临床意义，因为这种治疗可以立即 可转移到过敏性呼吸道疾病，如哮喘。

Allergic airway inflammation is a hallmark of asthma, one of the most common chronic diseases in the United States. The group 2 innate lymphoid cell (ILC2) is a recently described cell type that is a far more potent producer of IL-5 and IL-13 on a per cell basis than CD4+ Th2 cells, and there is increasing evidence that ILC2 are critical to the genesis and amplification of allergic inflammatory responses. In the last funding cycle of this VA Merit Award, we reported that prostaglandin (PG) I2 negatively regulates ILC2 function, both in vitro and in vivo, while inhibiting innate immunity-mediated airway eosinophilia, mucus metaplasia, and airways responsiveness, cardinal features of the asthma phenotype. Our novel in vivo preliminary data strongly suggests that PGI2 signaling inhibits Alt Ex-induced airway release of IL-33, an alarmin cytokine that binds to the ST2 receptor on ILC2 and other cells. Multiple genome wide association studies (GWAS) have identified IL-33 and ST2 as asthma susceptibility loci. The experiments in this application have important clinical relevance as the NIH- funded Severe Asthma Research Program (SARP) reported that gene expression for the PGI2 receptor (termed PTGIR) in epithelial brushings was among the genes to best differentiate patients with severe asthma from those with mild disease and healthy controls. In SARP, patients with severe asthma had significantly lower, but not absent) gene expression of the PGI2 receptor. The long-term objectives of this application are to determine the mechanisms by which decreased PGI2 receptor expression in the epithelium is associated with severe asthma (Aim 1) and define the molecular mechanisms by which endogenous PGI2 signaling and exogenous PGI2 inhibit ILC2 proliferation and function (Aim 2). Investigating the role of endogenous PGI2 is critical to understanding the effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the world, on the innate allergic immune response as these agents inhibit PGI2 production. Investigating the role of exogenous PGI2 is important to understand the potential effects of inhaled PGI2 or its analogs on the innate allergic immune response as such agents are FDA approved and currently used therapeutically for pulmonary hypertension, and therefore the use of which could be used to treat allergic respiratory diseases such as asthma. These studies are paradigm shifting because there are currently no known FDA approved negative regulators of aeroallergen-induced IL-33 release and our preliminary data strongly supports that PGI2 may be the first described. Investigating the role of endogenous PGI2 is critical to understanding the effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the world, on the innate allergic immune response as these agents inhibit PGI2 production. The proposed experiments will advance the field in that they will define how PGI2, an FDA approved agent currently used in pulmonary hypertension, controls the early innate allergic immune response. The current availability of PGI2 for human treatment highlights the clinical significance of our application, as this therapy could be immediately transferrable to allergic respiratory diseases such as asthma.