NLRX1 and MAVS in cigarette smoke-induced inflammation and alveolar remodeling

NLRX1 和 MAVS 在香烟烟雾诱发的炎症和肺泡重塑中的作用

基本信息

批准号：
8916210
负责人：
Min-Jong Kang
金额：
$ 42.85万
依托单位：
YALE UNIVERSITY
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：
2014-09-05 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916210
关键词：
Address Air Alveolar Alveolar Macrophages Antibodies Antiviral Agents Apoptosis Apoptotic Binding Caspase-1 Cell Death Cells Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Clinical Co-Immunoprecipitations Competitive Binding Complex DNA Damage Development Disease Progression Disease model Evaluation Fluorescence Freezing Gene Proteins Goals Health Human IL18 gene Immune Immunoblot Analysis In Vitro Inflammation Inflammatory Interferon Type I Interleukin-18 Interleukins Intervention Investigation Leucine-Rich Repeat Lung Lung diseases Mediating Medical Methodology Microscopic Mitochondria Modality Modeling Molecular Mus Nucleotides Outer Mitochondrial Membrane Pathway interactions Patients Pattern Pharmacologic Substance Play Pneumonia Production Proteins Pulmonary Emphysema Reactive Oxygen Species Research Respiratory physiology Role Severity of illness Signal Transduction Signaling Molecule Smoker Societies Structure of parenchyma of lung Syndrome Testing Therapeutic Transgenic Organisms United States Viral Virus cigarette smoke-induced cigarette smoking cohort helicase immune activation in vivo macrophage man mutant novel null mutation pathogen public health relevance research study response restoration

项目摘要

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) encompasses several clinical syndromes, most notably emphysema and chronic bronchitis. It is a major unmet medical need in the United States and worldwide and, in western society, is impressively associated with cigarette smoke (CS) exposure. We hypothesized that CS dysregulates RLH signaling, and the dysregulation of RLH signaling plays an important role in CS-induced inflammation and remodeling responses. To address this, we focused additional investigations on the molecules that regulate MAVS, especially mitochondrial molecules, because MAVS is bound to the mitochondrial outer membrane and its localization on mitochondria is critical for the proper functioning of MAVS. Intriguingly, our preliminary studies from our CS-induced murine emphysema model revealed that a novel mitochondrial molecule, nucleotide binding domain and leucine rich repeat containing protein X1 (NLRX1) that interacts with MAVS and inhibits MAVS-mediated production of type I interferons (IFNs) and NF?B signaling, was significantly suppressed in CS-exposed lungs. In addition, CS-induced significant activation of inflammasome(s) and the consequent interleukin1β (IL1β) and IL18 activation, induction of type I IFNs and pulmonary inflammation and emphysematous destruction; these responses were exaggerated in the absence of NLRX1, while ameliorated in the absence of MAVS. Importantly, the expression of NLRX1 is suppressed in lungs from three different human COPD cohorts. Furthermore, this suppression shows impressive correlation with the degree of airflow limitation, a hallmark of COPD, and other clinical variables related to disease severity. This constellation of findings has led us to the following multipart hypothesis and specific aims; Aim #1. Define the roles of MAVS and NLRX1 in CS-induced activation of inflammasome(s), induction of type I IFNs and pulmonary inflammatory and remodeling responses; Aim #2. Characterize the effects of CS on the expression of NLRX1 in mice, the alteration of the expression of NLRX1 in patients with COPD, and the role of NLRX1 in the inflammasome activation in macrophages; Aim #3. Determine the reactive oxygen species (ROS)dependent inhibition of NLRX1 against the assembly of inflammasome complex on MAVS in macrophages in vitro; Aim #4. Determine if restoring NLRX1 in vivo ameliorates CS-induced activation of inflammasome(s), induction of type I IFNs and pulmonary inflammatory and remodeling responses. With successful accomplishment of this project, we will define the roles of novel mitochondrial molecules called NLRX1 and MAVS in the development of COPD. In addition, we will test the possibility that interventions that restore suppressed NLRX1 or modulate this pathway may have therapeutic potential to ameliorate rapid decline of lung function as well as enhanced pulmonary inflammation in smokers and patients with COPD.

描述（由申请人提供）：慢性阻塞性肺病（COPD）包括多种临床综合征，最明显的是肺气肿和慢性支气管炎，它是美国和全世界未得到满足的主要医疗需求，并且在西方社会与香烟密切相关。我们探索了CS导致RLH信号传导失调，并且RLH信号传导失调在CS诱导的炎症和重塑反应中发挥着重要作用。为此，我们将更多的研究重点放在调节 MAVS 的分子上，特别是线粒体分子，因为 MAVS 与线粒体外膜结合，并且其在线粒体上的定位对于 MAVS 的正常功能至关重要。有趣的是，我们对 CS 诱导的初步研究。小鼠肺气肿模型揭示了一种新型线粒体分子、核苷酸结合域和富含亮氨酸重复序列的蛋白 X1 (NLRX1)，它与 MAVS 相互作用并抑制 MAVS 介导的 I 型干扰素的产生(IFN) 和 NF?B 信号传导在暴露于 CS 的肺部中显着受到抑制。此外，CS 诱导炎症小体的显着激活以及随后的白细胞介素 1β (IL1β) 和 IL18 激活，诱导 I 型 IFN 和肺部炎症。和肺气肿破坏；在没有 NLRX1 的情况下这些反应被夸大，而在没有 MAVS 的情况下这些反应得到改善。重要的是，NLRX1 的表达是此外，这种抑制与气流受限程度（COPD 的标志）以及与疾病严重程度相关的其他临床变量具有令人印象深刻的相关性。目标#1。明确 MAVS 和 NLRX1 在 CS 诱导的炎症小体激活、I 型 IFN 诱导以及肺部炎症和重塑反应中的作用；表征 CS 对小鼠 NLRX1 表达的影响、COPD 患者中 NLRX1 表达的变化以及 NLRX1 在巨噬细胞炎症小体激活中的作用；目标 #3 确定活性氧 (ROS) 依赖性。体外抑制 NLRX1 对巨噬细胞中 MAVS 上炎症小体复合物的组装；确定体内恢复 NLRX1 是否会改善； CS 诱导的炎症小体激活、I 型 IFN 的诱导以及肺部炎症和重塑反应。此外，随着该项目的成功完成，我们将确定称为 NLRX1 和 MAVS 的新型线粒体分子在 COPD 发展中的作用。，我们将测试恢复被抑制的 NLRX1 或调节该通路的干预措施可能具有改善吸烟者和 COPD 患者肺功能快速下降以及肺部炎症增强的治疗潜力的可能性。