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（由申请人提供）：Th17 细胞通过募集中性粒细胞受体相互作用蛋白 2 (Rip2)（细胞内肽聚糖传感器 Nod1 和 Nod2 使用的接头分子）提供针对某些（但不是全部）细菌感染的保护性免疫。在引导针对各种细菌的先天免疫反应中发挥重要作用 (1) 然而，Th17 细胞产生细胞因子 IL-17A、IL-17F 和IL-22 与皮肤（即牛皮癣）、肺部（即哮喘和 我们研究重要的人类病原体肺炎衣原体 (CP)，它与过敏性哮喘、慢性肺病、慢性阻塞性肺病恶化等慢性疾病有关。以及吸烟者动脉粥样硬化和肺癌等其他慢性炎症疾病的进展，我们之前发现肺泡巨噬细胞中的 Rip2 在控制 CP 感染中发挥着关键作用。然而，幸存的 Rip2-/- 小鼠出现了严重的慢性肺部炎症，包括肺纤维化增强。出乎意料的是，我们发现 Rip2 缺陷的 T 细胞本质上偏向于产生 Th17 和 IL-17A，这揭示了 Rip2 的新作用。我们的初步研究表明，在致病性（IL-1驱动的）Th17 分化的条件下， Rip2-/- T 细胞表现出增强的 Th17 分化和增加的视黄酸相关孤儿受体 α (RORα) 表达，这是一种导致 Th17 偏向的重要转录因子，我们的数据也支持 Rip2-/ 中出现的慢性炎症的假设。 - CP 感染后的小鼠是 Rip2-/- T 细胞中内在 Th17 倾斜缺陷的结果，与 IL-17 对细菌杀灭的作用无关。与人类各种 IL-17 驱动的慢性炎症性疾病（包括严重哮喘和克罗恩病）相关的多态性，我们将寻求确定这种新型 Rip2-Th17 调节轴在 T 细胞中的功能意义。提出以下研究，重点围绕以下中心假设：T 细胞中的 Rip2 缺陷本质上增强了 Th17 分化，从而在 CP 感染期间诱导慢性炎症，而 NODs/RIP2 的缺失通过增强为了检验这些假设，我们提出以下三个具体目标： 目标 1. 确定 IL-17 信号在 CP 感染和慢性肺部炎症和纤维化过程中的作用 目标 2. 确定 Rip2/IL 的作用。 CP 感染引起的慢性肺部炎症/肺纤维化中的 -17 轴以及人 Rip2 SNP 在 Th17 驱动疾病中 Th17 倾斜中的作用 目标 3. 研究分子目标。 Rip2 调节 Th17 分化的机制 在这些研究的结论中，我们期望能够描绘出 T 细胞中这种新型 Th17 调节途径，并确定治疗缓解 Th17 介导的慢性炎症性疾病的关键靶标。