Non-Classical Cytokine Secretion in Chronic Airway Disease

摘要 慢性下呼吸道疾病是美国和世界范围内发病率和死亡率的主要原因。 目前还没有有效的疾病修正疗法，而且还不清楚如何定义和优化 治疗哮喘和慢性阻塞性肺疾病(慢性阻塞性肺疾病； 慢性支气管炎和肺气肿)。这项机械研究的目的是定义新的路径服从于 基于病变的呼吸道上皮细胞作为慢性支气管炎上游驱动因素的治疗干预 呼吸道疾病。作为这一提议的基础，多项人类临床和翻译研究以及 过敏原、烟雾和病毒诱导的动物模型已经巩固了致病上皮细胞- 衍生细胞因子IL-33在COPD和哮喘中的作用然而，仍然存在的一个主要知识差距是理解 核隔绝的IL-33可从病变的呼吸道细胞中被激活和分泌的机制 以驱使发炎。在这里，我们展示了人类COPD呼吸道上皮细胞的初步数据 细胞表达水平增加的截短、剪接的IL-33亚型，它能够逃脱核 自动减支被大量地隐藏起来。我们的分析进一步揭示了这种分泌的IL-33的新特征 异构体，包括翻译后修饰，与外切体相关的伴侣相互作用，以及 利用外切体运输途径进行分泌。因此，本研究旨在阐明这一影响 在这些新发现的IL-33生物学特征中，IL-33与慢性呼吸道疾病的发病机制有关。目标1将 明确IL-33与胞外体伴侣蛋白相互作用如何促进细胞因子分泌和受体激活 为了驱动呼吸道疾病，使用人类细胞和小鼠呼吸道疾病模型，并在 人类呼吸道疾病标本。目标2将研究翻译后修饰在 通过类似的方法增加IL-33的分泌和受体的激活以传播疾病 使用人类细胞和小鼠模型，并在人类样本中进行验证。这些目标加在一起，将 解决引发和维持慢性呼吸道疾病的病理序列中的关键步骤，具有启发性 在粘膜界面靶向外切体介导的细胞因子分泌的新方法。

Abstract Chronic lower respiratory tract disease is a major cause of morbidity and mortality in the U.S. and worldwide. Currently there are no effective disease-modifying therapies and it remains unclear how to define and optimally treat disease endotypes within the spectrum of asthma and COPD (chronic obstructive pulmonary disease; chronic bronchitis and emphysema). This mechanistic research aims to define new pathways amenable to therapeutic intervention based on the role of diseased airway epithelial cells as an upstream driver of chronic airway disease. As a foundation for this proposal, multiple human clinical and translational studies as well as allergen- smoke- and virus-induced animal models have solidified the relevance of the pathogenic epithelial- derived cytokine IL-33 in COPD and asthma. However, a major knowledge gap that remains is understanding the mechanism by which nuclear-sequestered IL-33 can be activated and secreted from diseased airway cells to drive inflammation. Here we present preliminary data that demonstrates human COPD airway epithelial cells express increased levels of a truncated, spliced IL-33 isoform, which is capable of escaping nuclear sequestration to be abundantly secreted. Our analysis further revealed novel features of this secreted IL-33 isoform including post-translational modification, interaction with exosome-associated chaperones, and utilization of exosome trafficking pathways for secretion. Accordingly, this study aims to elucidate the impact of these newly-discovered features of IL-33 biology on the pathogenesis of chronic airway disease. Aim 1 will define how IL-33 interaction with exosomal chaperones enhances cytokine secretion and receptor activation to drive airway disease, using human cellular and mouse airway disease models coupled with validation in human airway disease specimens. Aim 2 will investigate the role of post-translational modification in augmenting IL-33 secretion and receptor activation to propagate disease, through an analogous approach using human cellular and mouse models with validation in human specimens. Together, these aims will address key steps in the pathologic sequence that initiates and sustains chronic airway disease, illuminating novel ways to target exosome-mediated cytokine secretion at the mucosal interface.