Interaction with Rip2 and Th17 in Chronic Inflammation

慢性炎症中 Rip2 和 Th17 的相互作用

• 批准号: 9217562
• 负责人: Moshe Arditi
• 金额: $ 43.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217562
• 关键词: Affect; Alpha Cell; Alveolar Macrophages; Asthma; Atherosclerosis; Bacteria; Bacterial Infections; Binding; Biological Models; Blood Platelets; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; Cations; Cells; Chlamydophila pneumoniae; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Crohn' s disease; Data; Defect; Development; Disease; Epithelial Cells; Exhibits; Extrinsic asthma; Fibrosis; Genetic Polymorphism; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic; Host Defense; Human; Immune response; Immunity; Incidence; Individual; Infection; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1; Interleukin-17; Investigation; Laboratories; Link; Lung; Lung Inflammation; Lung diseases; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Mycoses; Neutrophil Infiltration; Orphan; Pathogenesis; Pathogenicity; Peptidoglycan; Phosphotransferases; Play; Production; Psoriasis; Pulmonary Fibrosis; RIPK2 gene; Receptor-Interacting Serine/Threonine Protein Kinase 2; Regulation; Regulatory Pathway; Reporting; Risk; Role; Sarcoidosis; Signal Transduction; Single Nucleotide Polymorphism; Smoker; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tretinoin; base; cytokine; interleukin-22; killings; mouse Ripk2 protein; novel; pathogen; promoter; public health relevance; receptor; response; sensor; skin disorder; targeted treatment; transcription factor

 DESCRIPTION (provided by applicant): Th17 cells provide protective immunity against certain, but not all, bacterial infections through the recruitment of neutrophils. Receptor interacting protein 2 (Rip2), the adapter molecule used by the intracellular peptidoglycan sensors Nod1 and Nod2, plays an important role in directing innate immune responses against various bacteria (1). However, Th17 cells produce the cytokines IL-17A, IL-17F, and IL-22 that have been linked to chronic inflammatory diseases of skin (i.e., psoriasis), lung (i.e., asthma and chronic obstructive pulmonary disease), and gut (i.e., Crohn's disease). We study the important human pathogen, Chlamydia pneumoniae (CP) that has been associated with chronic conditions such as allergic asthma, chronic lung diseases, exacerbation of chronic obstructive pulmonary disease, and as well as the progression of other chronic inflammatory diseases such as atherosclerosis and lung cancer in smokers. We previously found that Rip2 in alveolar macrophages played a critical role in controlling CP infection in mice, yet surviving Rip2-/- mice developed a profound chronic lung inflammation including enhanced lung fibrosis (2). Unexpectedly, we found that Rip2-deficient T cells were intrinsically skewed towards Th17 and IL-17A production, revealing a novel role for Rip2 in regulating Th17 differentiation. Our preliminary studies show that under conditions of pathogenic (IL-1-driven) Th17 differentiation, Rip2-/- T cells exhibit enhanced Th17 differentiation and increased expression of retinoic acid-related orphan receptor alpha (RORα), an important transcription factor that contributes to Th17 skewing. Our data also support the hypothesis that the chronic inflammation seen in Rip2-/- mice after CP infection is a result of the intrinsic Th17 skewing defect in Rip2-/- T cells, independent of IL-17 effects on bacterial killing. Given the increasing identification of NOD/Rip2 polymorphisms associated with various IL-17-driven chronic inflammatory diseases in humans, including severe asthma and Crohn's disease, we will seek to determine the functional implications of this novel Rip2-Th17 regulatory axis in T cells. Based upon these key novel findings, we propose the following studies focused around the central hypothesis that Rip2 deficiency in T cells intrinsically enhances Th17 differentiation, thereby inducing chronic inflammation during CP infection, and that deletion of NODs/RIP2 increases Th17 skewing through enhanced RORα activity. To test these hypotheses, we propose the following three Specific Aims: Aim 1. To determine the role of IL- 17 signaling during CP infection and chronic lung inflammation and fibrosis. Aim 2. To determine the role of the Rip2/IL-17 axis in CP infection-induced chronic lung inflammation/lung fibrosis and the role of human Rip2 SNPs in Th17 skewing in Th17-driven disease. Aim 3. To investigate the molecular mechanisms by which Rip2 regulates Th17 differentiation. At the conclusion of these studies, we expect to have delineated this novel Th17 regulatory pathway in T cells and have identified key targets for therapeutically mitigating Th17-mediated chronic inflammatory diseases.

 描述（由适用提供）：TH17细胞通过募集中性粒细胞提供了受保护的免疫因子，可抵抗某些但不是全部的细菌感染。受体相互作用的蛋白2（RIP2）是由细胞内粘液胶囊传感器NOD1和NOD2使用的衔接子分子，在指导针对各种细菌的先天免疫调查中起着重要作用（1）。然而，Th17细胞产生了与皮肤（即牛皮癣），肺（即哮喘和哮喘和哮喘和哮喘和肺部）相关的与皮肤慢性炎性疾病有关的IL-17A，IL-17F和IL-22 慢性阻塞性肺疾病）和肠道（即克罗恩病）。我们研究了与慢性疾病（如过敏性哮喘，慢性肺部疾病，慢性阻塞性肺部疾病的加剧，以及其他慢性炎性疾病的进展，如烟雾者和烟雾癌中的其他慢性炎症性疾病的进展）有关的重要人类病原体（CP），例如过敏性哮喘，慢性肺部疾病，慢性阻塞性肺部疾病的加剧。我们先前发现，肺泡巨噬细胞中的RIP2在控制小鼠的CP感染中起着至关重要的作用，但幸存的RIP2 - / - 小鼠产生了深刻的慢性肺部感染，包括增强的肺纤维化（2）。出乎意料的是，我们发现RIP2缺陷T细胞本质上偏向TH17和IL-17A的产生，揭示了RIP2在调节Th17分化中的新作用。我们的初步研究表明，在致病性（IL-1驱动）的条件下，Th17分化， RIP2 - / - T细胞表现出增强的Th17分化和视黄酸相关的孤儿受体α（RORα）的表达增加，这是有助于Th17偏斜的重要转录因子。我们的数据还支持以下假设：CP感染后RIP2 - / - 小鼠中看到的慢性感染是RIP2 - / - T细胞中固有的Th17偏斜缺陷的结果，与IL-17对细菌杀死的影响无关。鉴于对与人类各种IL-17驱动的各种慢性炎症性疾病有关的NOD/RIP2多态性的鉴定增加，包括严重的哮喘和克罗恩病，我们将寻求确定T细胞中这种新型RIP2-TH17调节轴的功能含义。基于这些关键的新发现，我们提出了以下研究围绕中心假设的研究，即T细胞的RIP2缺乏源在CP感染期间内在增强了Th17的分化，从而诱导了慢性炎症，而NODS/RIP2的缺失通过增强的RORα活性增加。为了检验这些假设，我们提出以下三个特定目的：目标1。确定IL-17信号在CP感染和慢性肺部感染和纤维化过程中的作用。目标2。确定RIP2/IL-17轴在CP感染引起的慢性肺部感染/肺纤维化以及人RIP2 SNP在Th17偏斜中的作用在Th17驱动疾病中的作用。目的3。研究RIP2调节Th17分化的分子机制。在这些研究的结论中，我们预计将描绘出T细胞中这种新型TH17调节途径，并确定了治疗方法可减轻Th17介导的慢性炎症性疾病的关键靶标。