Functional plasticity of Th17 in arthritis

Th17 在关节炎中的功能可塑性

基本信息

批准号：
10201506
负责人：
Nunzio Bottini
金额：
$ 19.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-24 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201506
关键词：
Address Antigens Applications Grants Arthritis Arthritogenic Autoimmune Backcrossings Bacterial Infections Behavior Biology CD4 Positive T Lymphocytes Cells Coculture Techniques Congenic Mice Data Development Disease Distant Drug Targeting FOXP3 gene Fibroblasts Future Genes Genetic Recombination Goals Grant Haplotypes Heterogeneity Human IL7 gene Immune Immunosuppression Inbred BALB C Mice Infection Inflammation Interferon Type II Interleukin-1 Receptors Interleukin-10 Interleukin-17 Interleukins Joints Knock-in Knock-out Knowledge Laboratories Lung Mediating Mesenchymal Mining Modeling Molecular Mus Mutation Pathogenesis Pathogenicity Pathologic Patients Pattern Phenotype Play Population Predisposition Production Psoriatic Arthritis Reporter Reporting Rheumatoid Arthritis Role Severity of illness Skin Source Stimulus Synovial Membrane Synovitis T-Lymphocyte Subsets Techniques Time arthritis therapy autoimmune arthritis autoimmune inflammation cell motility design experimental study functional plasticity genetic manipulation high risk immunoregulation joint inflammation mouse model neuroinflammation novel overexpression peripheral blood personalized medicine promoter receptor single-cell RNA sequencing sphingosine 1-phosphate

项目摘要

ABSTRACT The objective of this grant application is to explore the plasticity of Th17 in arthritis. Interleukin-17A (IL-17A) producing Th17 are present often in large numbers in the synovium of patients with rheumatoid and psoriatic arthritis. However, targeting of IL17A is generally insufficient to fully control joint inflammation in these conditions. One potential scenario is that in the context of worsening joint inflammation, Th17 undergo conversion into pathogenic IL17A-negative cell populations, collectively called exTh17. The conversion of Th17 into exTh17 has been documented in the context of neuroinflammation and infections, and locally produced IL-7 was described as a key promoter of Th17 plasticity in the lung. However, the occurrence of Th17 plasticity in arthritis and its potential role in perpetuating synovial inflammation remain unknown. We generated a novel fate-mapping mouse model of autoimmune arthritis, which allows to follow the conversion of Th17 into exTh17, and collected preliminary data suggesting that Th17 undergo significant loss of IL17A expression and conversion into exTh17 in the context of synovial inflammation. We also identified candidate exTh17 subpopulations which might contribute to perpetuate joint inflammation despite their loss of IL17A expression. Here we will leverage our mouse model to collect pilot evidence about the immunoregulatory and/or pathogenic role of exTh17 in synovial autoimmune inflammation (Aim 1). Also, we will explore whether IL-7 or other factors produced by synovial fibroblast play a role in inducing conversion of Th17 into exTh17 (Aim 2). Our long-term goal is to leverage knowledge of local immune cell phenotypes at various stages of disease to enable stage-specific and personalized therapies of arthritis to minimize non specific immunosuppression.

抽象的该赠款应用的目的是探索Th17在关节炎中的可塑性。白介素17a（IL-17A）在类风湿和银屑病患者的滑膜中，产生的Th17经常存在很大数量关节炎。但是，在这些条件下，IL17A的靶向通常不足以完全控制关节炎症。一种潜在的情况是，在关节炎症恶化的背景下，Th17经历了转换为致病性IL17A阴性细胞群，统称为Exth17。 Th17转换为Exth17 描述了在神经炎症和感染的背景下，描述了局部产生的IL-7 作为肺中Th17可塑性的关键启动子。但是，Th17可塑性在关节炎及其潜在的连续性滑膜炎症的作用尚不清楚。我们产生了一种新型的自身免疫性关节炎的命运鼠标模型，该模型允许遵循转换 Th17到Exth17的最初数据，表明TH17遭受了IL17A的重大损失在滑膜炎症的背景下，表达和转化为ExTH17。我们还确定了候选人 Exth17亚群，尽管IL17A损失了，但可能导致关节炎症永久存在表达。在这里，我们将利用鼠标模型收集有关免疫调节和/或的试点证据 Ex17在滑膜自身免疫性炎症中的致病作用（AIM 1）。另外，我们将探讨IL-7还是滑膜成纤维细胞产生的其他因素在诱导Th17转化为Exth17（AIM 2）中起作用。我们的长期目标是利用疾病各个阶段的局部免疫细胞表型的了解使关节炎的特定阶段和个性化疗法可最大程度地减少非特异性免疫抑制。