Pathogenic role of ILC2 in rheumatoid arthritis

ILC2 在类风湿性关节炎中的致病作用

• 批准号: 10057498
• 负责人: GARY S FIRESTEIN
• 金额: $ 20.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057498
• 关键词: Acute; Aggressive behavior; Amphiregulin; Anti-Inflammatory Agents; Antigen Receptors; Antirheumatic Agents; Applications Grants; Arthritis; Attitude; B-Lymphocytes; Behavior; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Classification; Complex; Cytotoxic T-Lymphocytes; Development; Disease; Disease Management; Disease remission; Epidermal Growth Factor; Fibroblasts; Fibrosis; Flare; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune; Immune response; Immunologics; In Vitro; Infection; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Joints; K/BxN model; Knockout Mice; Knowledge; Lymphoid Cell; Mediating; Mesenchymal; Modeling; Mus; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Phase; Play; Population; Production; Reporting; Research; Research Personnel; Resolution; Rheumatoid Arthritis; Role; Severities; Stromal Cells; Synovial Membrane; T-Lymphocyte; Th2 Cells; Therapeutic Agents; Time; Tissues; Work; cartilage degradation; cytokine; experimental study; high risk; immune function; in vivo; joint destruction; joint inflammation; macrophage; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; receptor; reconstitution; recruit; response; systemic autoimmune disease; targeted treatment; tumor

ABSTRACT The pathogenesis of rheumatoid arthritis (RA) involves a complex interplay between adaptive (e.g. T & B cells) and innate (e.g. macrophages) immune cells and mesenchymal-derived stromal cells (e.g. local fibroblast-like synoviocytes [FLS]). Immune cell-mediated activation of FLS plays a key role in joint inflammation and destruction during RA. This project will explore a novel mechanism of activation of FLS by the ILC2 subset of innate lymphoid cells (ILCs). ILCs are recently discovered immune cells that are enriched in peripheral tissues and act as the first local barrier against infections and tumors. Four major subsets of ILCs have been identified, ILC1, ILC2, ILC3 and cNK cells that display immune functions similar to those of Th1, Th2, and Th17 subsets of CD4 T cells and CD8 killer T cells respectively. Of these, ILC2 are homologous to Th2 cells and secrete “type 2 cytokines” such as interleukin-4 (IL-4), IL-5 and IL-13, which drive a “type 2” immune response. The type 2 immune response is considered to be anti-inflammatory in RA, however it remains unclear whether ILC2 exclusively play a disease protective role in RA. The objective of this grant is to collect pilot evidence that ILC2 play a pathogenic role in RA by secreting an epidermal growth factor (EGF)-similar molecule called amphiregulin (AREG). ILC2 are known to secrete AREG which normally helps to maintain tissue integrity in response to infections, but is also implicated in the pathogenesis of organ fibrosis in the context of chronic inflammation. We have found high levels of AREG -mainly produced by ILC2- in the joints of arthritic mice and have preliminary evidence that AREG promotes arthritis severity and the aggressive behavior of fibroblast-like synoviocytes (FLS) in vitro. We thus hypothesize that joint-localized ILC2 promote disease activity in RA through interaction with FLS via production of AREG. This grant application proposes experiments aimed to obtain rigorous evidence that ILC2 enhance development of arthritis in mice through production of AREG (Aim 1), and that AREG promotes aggressive and joint-destructive behavior in FLS in vitro and in vivo (Aim 2). The project fits well with the R21 format because the objective is to collect pilot evidence in support of a concept that is currently considered high risk and potentially counterintuitive, however, if validated, it might pave the way to novel therapeutic approaches to RA via interference with the ILC2-AREG-FLS axis. .

摘要 类风湿关节炎(RA)的发病机制涉及适应性(如T&B细胞)之间复杂的相互作用。 和先天免疫细胞(如巨噬细胞)和间质来源的基质细胞(如局部成纤维细胞样细胞 滑膜细胞[FLS])。免疫细胞介导的FLS激活在关节炎症和炎症中起关键作用 风湿性关节炎期间的破坏。本项目将探索一种由ILC2子集激活FLS的新机制 先天淋巴样细胞(ILCs)。ILC是最近发现的一种免疫细胞，富含在周围组织中。 并成为抵御感染和肿瘤的第一道局部屏障。已经确定了ILC的四个主要子集， 表现出与Th1、Th2和Th17亚群相似的免疫功能的ILC1、ILC2、ILC3和CNK细胞 分别为CD4T细胞和CD8杀伤T细胞。其中ILC2与Th2细胞同源，分泌 白介素4(IL-4)、白介素5(IL-5)和白介素13(IL-13)等“2型细胞因子”，驱动“2型”免疫反应。这个 2型免疫反应被认为是RA的抗炎反应，但目前尚不清楚ILC2是否 独家发挥对RA的疾病保护作用。这笔赠款的目的是收集试点证据，证明ILC2 通过分泌一种与表皮生长因子(EGF)类似的分子在RA中发挥致病作用 安非他明(AREG)。已知ILC2分泌AREG，它通常有助于维持组织的完整性 对感染的反应，但也与慢性器官纤维化的发病机制有关 发炎。我们在关节炎小鼠和小鼠的关节中发现了高水平的AREG-主要由ILC2产生 有初步证据表明AREG促进了关节炎的严重程度和成纤维细胞样的侵袭行为 滑膜细胞(FLS)。因此我们假设联合定位的ILC2促进类风湿关节炎的疾病活动 通过生产AREG与FLS相互作用。这项拨款申请提出的实验旨在 获得ILC2通过产生AREG(AIM)促进小鼠关节炎发展的严格证据 1)，AREG在体外和体内促进FLS的攻击性和联合破坏性行为(目标2)。这个 该项目非常适合R21格式，因为其目标是收集支持某一概念的试点证据 这目前被认为是高风险和潜在的违反直觉的，然而，如果得到验证，它可能会为 通过对ILC2-AREG-FLS轴的干扰，为RA的新治疗方法铺平道路。 。