Interaction with Rip2 and Th17 in Chronic Inflammation

 描述(由申请人提供)：Th17细胞通过招募中性粒细胞来提供对某些但不是所有细菌感染的保护性免疫。受体相互作用蛋白2(RIP2)是细胞内肽聚糖传感器Nod1和NOD2使用的适配器分子，在引导针对各种细菌的天然免疫反应方面发挥着重要作用。然而，Th17细胞产生的细胞因子IL-17A、IL-17F和IL-22与皮肤(即牛皮癣)、肺(即哮喘和哮喘)的慢性炎症性疾病有关。 慢性阻塞性肺疾病)和肠道疾病(即克罗恩病)。我们研究了重要的人类病原体肺炎衣原体(CP)，它与过敏性哮喘、慢性肺部疾病、慢性阻塞性肺疾病的加重以及其他慢性炎症性疾病的进展有关，如吸烟者的动脉粥样硬化和肺癌。我们之前发现，肺泡巨噬细胞中的RIP2在控制小鼠肺炎衣原体感染方面发挥了关键作用，但存活的RIP2-/-小鼠出现了严重的慢性肺部炎症，包括肺纤维化增强(2)。出乎意料的是，我们发现RIP2缺陷的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)Th17分化的条件下， RIP2-/-T细胞表现出增强的Th17分化和维甲酸相关孤儿受体α(RoRα)的表达增加，这是导致Th17偏斜的重要转录因子。我们的数据还支持这样的假设，即CP感染后RIP2-/-小鼠出现的慢性炎症是RIP2-/-T细胞固有的Th17扭曲缺陷的结果，与IL-17对细菌杀伤的影响无关。鉴于越来越多的人发现NOD/RIP2基因多态性与各种IL-17驱动的慢性炎症性疾病有关，包括严重的哮喘和克罗恩病，我们将试图确定这一新的RIP2-Th17调节轴在T细胞中的功能意义。基于这些重要的新发现，我们围绕以下中心假设提出以下研究：T细胞中RIP2缺乏本质上促进了Th17的分化，从而在CP感染过程中引发慢性炎症；NODS/RIP2缺失通过增强RoRα活性增加了Th17的偏斜。为了验证这些假说，我们提出了以下三个具体目标：目的1.确定IL-17信号在肺炎衣原体感染和慢性肺部炎症和纤维化中的作用。目的2.探讨RIP2/IL-17轴在肺炎衣原体感染诱导的慢性肺炎症/肺纤维化中的作用，以及人类RIP2单核苷酸多态在Th17驱动的疾病中的Th17偏斜中的作用。目的3.探讨RIP2调节Th17细胞分化的分子机制。在这些研究的结论中，我们希望在T细胞中描绘出这一新的Th17调节途径，并确定用于治疗减轻Th17介导的慢性炎症性疾病的关键靶点。

 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.