Novel function of MUC18: amplification of inflammation in allergic lungs

MUC18的新功能：放大过敏性肺部的炎症

基本信息

批准号：
9189643
负责人：
Hong W Chu
金额：
$ 39.63万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-22 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189643
关键词：
Acute Adaptor Signaling Protein Affect Age Agonist Allergens Allergic Alpha Cell Alveolar Macrophages Asthma Automobile Driving Bacteria Bacterial Infections Bone Marrow Cell Adhesion Molecules Cell Culture Techniques Cells Cessation of life Chimera organism Cytoplasmic Tail Data Endothelial Cells Eotaxin Epithelial Epithelial Cells Genes Glycoproteins Goals Healthcare Human IL8 gene In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukin-13 Knock-out Knockout Mice Knowledge Link Lung Lung Inflammation Lung diseases MCAM gene Mediating Mitogen-Activated Protein Kinases Molecular Mus Mycoplasma pneumonia infection Mycoplasma pneumoniae Neoplasm Metastasis Pathway interactions Patients Phosphorylation Phosphorylation Site Plicamycin Population Production Proteins Radiation Receptor Signaling Research Respiratory Tract Infections Rhinovirus Role Serine Signal Pathway Small Interfering RNA Smooth Muscle Myocytes Specificity TIRAP gene TNF gene Testing Toll-like receptors Transgenic Mice United States Up-Regulation Viral Virus Diseases Work airway inflammation asthmatic asthmatic airway base cell type chemokine cost cytokine high risk improved in vivo inhibitor/antagonist innovation knock-down macrophage melanoma mouse model mutant neutrophil novel novel strategies overexpression pathogen prevent public health relevance response transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to determine if MUC18 enhances pro-inflammatory responses to viral and bacterial infections in allergic lungs. MUC18 is a transmembrane glycoprotein that is normally expressed on endothelial cells and smooth muscle cells. We have generated highly novel data linking MUC18 to the elaboration of pro- inflammatory cytokines in airway epithelial cells and alveolar macrophages that are exposed to IL-13 (a key Th2 cytokine in asthma). We identified a significant increase of MUC18 in human asthmatic airway epithelial cells and alveolar macrophages, and induction of MUC18 in these cell types by IL-13. By using MUC18 knockout, knockdown or over-expression approaches, we discovered that MUC18 enhances airway epithelial and lung macrophage pro-inflammatory cytokine (e.g., IL-8 and TNF-α production in response to human rhinovirus, various strains of bacteria and Toll-like receptor (TLR) agonists. Importantly, MUC18 knockdown in IL-13-exposed mouse lungs significantly reduced inflammation (neutrophils and chemokine KC) following bacterial infection. Finally, we have identified MUC18 specific intracellular phosphorylation sites that regulate its function. Our innovative research in MUC18 leads to the hypothesis that MUC18 up-regulation in allergic lungs amplifies inflammatory responses to various pathogens, leading to asthma exacerbations. Aim 1 will determine the mechanisms of MUC18 up-regulation by pathogens in allergic lungs. By using primary human airway epithelial cells and lung macrophages, mouse models of IL-13 exposure and viral/bacterial infection, and gene knock-down and overexpression strategies, we will test if pathogen infection activates mitogen-activated protein kinases through TLR signaling, which subsequently increases the activity of transcription factor specificity protein 1, and amplifies MUC18 up-regulation in Th2 cytokine-exposed lung cells. Aim 2 will define the pro-inflammatory function of MUC18 up-regulation during viral and bacterial infection. By using primary human cell cultures, mouse models of allergen exposure and viral/bacterial infection, and MUC18 conditional knockout mice, we will test the hypothesis that MUC18 up-regulation in allergic lungs promotes pro-inflammatory responses to pathogen infection. Aim 3 will dissect the mechanisms of MUC18 pro-inflammatory function. By using MUC18 mutants and transgenic mice over-expressing human wild-type MUC18 and a human MUC18 mutant, we will test the hypothesis that following pathogen-mediated activation of mitogen-activated protein kinases, MUC18 cytoplasmic tail is phosphorylated, resulting in NF-κB activation and amplified production of pro-inflammatory cytokines (e.g., IL-8 and eotaxin). Completion of our proposed studies will greatly improve our understanding about MUC18 pro-inflammatory function during various viral and bacterial infections in asthma. Our research findings will provide new and broad strategies (e.g., anti-MUC18 therapy) to prevent and treat acute exacerbations of asthma.

描述（由申请人提供）：本提案的目的是确定 MUC18 是否增强过敏性肺部对病毒和细菌感染的促炎反应。 MUC18 是一种通常在内皮细胞和平滑肌细胞上表达的跨膜糖蛋白。生成了高度新颖的数据，将 MUC18 与暴露于 IL-13 的气道上皮细胞和肺泡巨噬细胞中促炎细胞因子的形成联系起来（哮喘中的关键 Th2 细胞因子）。我们通过使用 MUC18 敲除、敲低或过度表达方法，发现人哮喘气道上皮细胞和肺泡巨噬细胞中 MUC18 显着增加，并诱导这些细胞类型中的 MUC18。，我们发现 MUC18 可以增强气道上皮细胞和肺巨噬细胞促炎细胞因子（例如，IL-8 和 TNF-α 的产生，以响应人类重要的是，IL-13 暴露小鼠肺部的 MUC18 敲低显着减少了细菌感染后的炎症（中性粒细胞和趋化因子 KC）。网站我们对 MUC18 的创新研究得出这样的假设：过敏性肺部中 MUC18 的上调会放大对各种病原体的炎症反应，导致哮喘恶化。目标 1 将确定过敏性肺部中病原体上调 MUC18 的机制。通过使用原代人气道上皮细胞和肺巨噬细胞、IL-13暴露和病毒/细菌感染的小鼠模型以及基因敲除和过度表达策略，我们将测试病原体感染是否通过 TLR 信号传导激活丝裂原激活蛋白激酶，从而增加转录因子特异性蛋白 1 的活性，并放大暴露于 Th2 细胞因子的肺细胞中 MUC18 的上调，目标 2 将定义促炎功能。通过使用原代人类细胞培养物、过敏原暴露和病毒/细菌感染的小鼠模型以及MUC18条件敲除小鼠，我们将测试病毒和细菌感染期间MUC18上调的情况。过敏性肺部中 MUC18 的上调促进对病原体感染的促炎症反应这一假设将通过使用 MUC18 突变体和过度表达人类野生型 MUC18 的转基因小鼠和人类来剖析 MUC18 促炎症功能的机制。 MUC18 突变体，我们将测试以下假设：在病原体介导的丝裂原激活蛋白激酶激活后，MUC18 胞质尾部被磷酸化，从而导致NF-κB 激活和促炎细胞因子（例如 IL-8 和嗜酸细胞活化趋化因子）的扩增将极大地提高我们对哮喘各种病毒和细菌感染期间 MUC18 促炎功能的了解。将提供新的、广泛的策略（例如抗MUC18疗法）来预防和治疗哮喘急性发作。