Function of the IL-18-IL-18R1-IFN-T2 Cytokine Eosinophil Axis in Asthma

项目摘要 调节哮喘气道炎症的过程尚不完全清楚， 尽管有目前的治疗，但经常有持续的气道炎症和疾病控制不良， 我们需要确定新的途径，并为患有不受控制的疾病的患者开发新的疗法。最近 研究表明，气道上皮细胞参与哮喘的发病机制，特别是气道上皮细胞与气道上皮细胞之间的相互作用。 上皮细胞和先天免疫细胞，用于调节对吸入过敏原的免疫应答， 哮喘的诱因我们最近发现嗜酸性粒细胞（EOS）的数量增加嵌入在 哮喘受试者的气道壁，并确定了EOS浸润上皮之间的关键关联 哮喘的一个具体特征是内源性气道高反应性（AHR）， 以及气道炎症的标志物。上皮刷拭的RNA测序（RNA-seq）分析， 捕获上皮细胞和浸润上皮的白细胞，从同一队列中获得， 患者显示编码干扰素（IFN）-γ（IFNG）和白细胞介素（IL）-18的基因表达增加 内源性AHR和上皮内EOS受试者中IL 18受体1（IL 18 R1）的水平。先前的研究 IL-18、IL-18 R1和IFN-γ与哮喘的AHR和气道炎症有关，已知IL-18可诱导 IFN-γ和2型（T2）细胞因子在多种细胞类型中的作用，但尚未在EOS中进行研究。基于这些 哮喘患者上皮内EOS和AHR之间的相关性，我们假设IL-18诱导 EOS通过IL-18 R1表达和产生IFN-γ和T2细胞因子，从而增强AHR并促进气道 炎症本研究的主要目的是建立小鼠模型系统和人气道 上皮-EOS共培养模型，以检查IL-18-IL-18 R1-IFN-γ-T2细胞因子的作用 在哮喘动物模型中，探讨EOS轴的功能。这些 研究将产生关键数据，作为指导职业发展的基础 该奖项进一步探索了这一途径。在目标1中，我们关注IL-18 R1在驱动AHR中的作用， 使用哮喘的小鼠模型来观察气道炎症，并特别检查IL-18 R1在小鼠哮喘中的作用。 肺EOS。目的2：研究人外周血EOS中IL-18-IL-18 R1-IFN-γ-T2细胞因子轴的特征 并检查这种炎症级联反应在EOS和人体气道之间的串扰中的作用 上皮这些研究的完成将提供对IL-18-IL-18 R1-IFN-γ-T2 细胞因子EOS轴及其在哮喘AHR和气道炎症中的作用， 关于这一主题的指导职业发展奖的令人信服的初步数据。

PROJECT SUMMARY The processes that regulate airway inflammation in asthma are not fully understood and patients with asthma often have persistent airway inflammation and poor disease control despite current therapies, highlighting the need to identify novel pathways and develop new therapies for patients with uncontrolled disease. Recent studies have implicated the airway epithelium in asthma pathogenesis, particularly interactions between the epithelium and innate immune cells that serve to regulate the immune response to inhaled allergens and other triggers for asthma. We recently identified increased numbers of eosinophils (EOS) embedded within the airway wall of subjects with asthma and identified key associations between EOS infiltrating the epithelium (“intraepithelial EOS”) and endogenous airway hyperresponsiveness (AHR), a specific feature of asthma, as well as markers of airway inflammation. RNA-sequencing (RNA-seq) analysis of epithelial brushings, which capture both epithelial cells and leukocytes infiltrating the epithelium, obtained from this same cohort of patients revealed increased expression of genes encoding interferon (IFN)- (IFNG) and interleukin (IL)-18 receptor 1 (IL18R1) amongst subjects with endogenous AHR and intraepithelial EOS. Previous studies have implicated IL-18, IL-18R1, and IFN- in AHR and airway inflammation in asthma and IL-18 is known to induce both IFN- and type 2 (T2) cytokines in multiple cell types but has not been studied in EOS. Based on these associations between intraepithelial EOS and AHR in humans with asthma, we hypothesize that IL-18 induces EOS to express and produce IFN- and T2 cytokines via IL-18R1, which enhances AHR and promotes airway inflammation. The major goal of this research is to develop a murine model system and human airway epithelium-EOS coculture model in order to examine the role of the IL-18-IL-18R1-IFN--T2 cytokine axis in EOS and explore the function of this axis using in vivo and ex vivo models of asthma. These studies will generate critical data that will serve as the foundation for a mentored career development award that further explores this pathway. In Aim 1, we focus on the role of IL-18R1 in driving AHR and airway inflammation using a murine model of asthma and specifically examine the role of IL-18R1 in murine lung EOS. In Aim 2, we characterize the IL-18-IL-18R1-IFN--T2 cytokine axis in human peripheral blood EOS and examine the role of this inflammatory cascade in the crosstalk between EOS and the human airway epithelium. Completion of these studies will provide a better understanding of the IL-18-IL-18R1-IFN--T2 cytokine EOS axis and its contribution to AHR and airway inflammation in asthma as well as provide compelling preliminary data for a mentored career development award on this topic.