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.

抽象的本次拨款申请的目的是探索 Th17 在关节炎中的可塑性。白介素-17A (IL-17A) 产生 Th17 的细胞通常大量存在于类风湿病和银屑病患者的滑膜中关节炎。然而，在这些情况下，靶向 IL17A 通常不足以完全控制关节炎症。一种可能的情况是，在关节炎症恶化的情况下，Th17 会转化为致病性 IL17A 阴性细胞群，统称为 exTh17。 Th17 转化为 exTh17 在神经炎症和感染的背景下已被记录，并且描述了本地产生的 IL-7 作为肺部 Th17 可塑性的关键促进者。然而，Th17可塑性在关节炎中的发生及其在滑膜炎症持续存在中的潜在作用仍不清楚。我们生成了一种新型的自身免疫性关节炎命运图谱小鼠模型，该模型可以跟踪转化 Th17 转化为 exTh17，并收集了初步数据，表明 Th17 经历了 IL17A 的显着损失在滑膜炎症中表达并转化为 exTh17。我们还确定了候选人尽管 IL17A 缺失，但 exTh17 亚群仍可能导致关节炎症持续存在表达。在这里，我们将利用我们的小鼠模型来收集有关免疫调节和/或 exTh17 在滑膜自身免疫性炎症中的致病作用（目标 1）。此外，我们还将探讨 IL-7 或滑膜成纤维细胞产生的其他因子在诱导 Th17 转化为 exTh17 中发挥作用（目标 2）。我们的长期目标是利用疾病各个阶段局部免疫细胞表型的知识来实现关节炎的阶段特异性和个性化治疗，以尽量减少非特异性免疫抑制。