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

项目总结 哮喘中调节呼吸道炎症的过程尚不完全清楚，哮喘患者 尽管有目前的治疗方法，但通常有持续性的呼吸道炎症和较差的疾病控制，突出了 需要为无法控制的疾病患者确定新的途径和开发新的治疗方法。近期 研究表明，呼吸道上皮细胞参与了哮喘的发病机制，特别是两者之间的相互作用。 调节吸入性变应原和其他过敏原的免疫反应的上皮和先天免疫细胞 哮喘的诱因。我们最近发现，植入体内的嗜酸性粒细胞(EOS)数量增加 哮喘患者的气道壁和嗜酸性粒细胞渗入上皮之间的关键关联 (“上皮内EOS”)和内源性气道高反应性(AHR)，这是哮喘的一个特殊特征，AS 以及呼吸道炎症的标记物。上皮刷的RNA测序(RNA-seq)分析， 捕获上皮细胞和渗入上皮的白细胞，从同一队列中获得 患者表现出编码干扰素和白介素18的基因表达增加 内源性AHR和上皮内EOS受试者的受体1(IL18R1)之前的研究已经 IL-18、IL-18R1和干扰素-参与哮喘的过敏性反应和呼吸道炎症，已知IL-18可诱导 干扰素-和2型(T2)细胞因子都存在于多种细胞类型中，但尚未在嗜酸性粒细胞中进行研究。基于这些 哮喘患者上皮内EOS和AHR之间的关系，我们假设IL-18诱导 Eos通过IL-18R1表达和产生干扰素-和T2细胞因子，增强AHR，促进呼吸道 发炎。这项研究的主要目标是开发一种小鼠模型系统和人类呼吸道 上皮-EOS共培养模型检测IL-18-IL-18R1-干扰素--T2细胞因子的作用 AXIS在EOS中的作用，并利用哮喘的体内和体外模型来探索该轴的功能。这些 研究将产生关键数据，作为指导职业发展的基础 进一步探索这条道路的奖项。在目标1中，我们重点研究了IL-18R1在AHR和AHR中的作用 哮喘小鼠模型的气道炎症及IL-18R1在小鼠中的作用 肺EOS。在目标2中，我们鉴定了人外周血EOS中IL-18-IL-18R1-干扰素--T2细胞因子轴的特征 并研究这种炎性级联在EOS和人类呼吸道之间的串扰中所起的作用 上皮组织。这些研究的完成将提供对IL-18-IL-18R1-干扰素--T2的更好的了解 细胞因子EOS轴及其在哮喘AHR和呼吸道炎症中的作用 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.