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: 10269026
• 负责人: GARY S FIRESTEIN
• 金额: $ 16.86万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269026
• 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. .

抽象的 类风湿关节炎（RA）的发病机理涉及自适应之间的复杂相互作用（例如T＆B细胞） 和先天性（例如巨噬细胞）免疫细胞和间充质衍生的基质细胞（例如局部成纤维细胞样 滑膜细胞[FLS]）。免疫细胞介导的FLS激活在关节注射中起关键作用 RA期间的破坏。该项目将通过ILC2子集探索一种新型FLS激活的机理 先天淋巴样细胞（ILC）。 ILC最近被发现富含周围组织的免疫细胞 并充当针对感染和肿瘤的第一个局部障碍。已经确定了四个主要的ILC子集， ILC1，ILC2，ILC3和CNK细胞显示出与Th1，Th2和Th17子集相似的免疫功能 CD4 T细胞和CD8杀伤T细胞的摄入。其中，ILC2与Th2细胞同源和秘密 “ 2型细胞因子”，例如白介素4（IL-4），IL-5和IL-13，它们驱动“ 2型”免疫反应。这 2型免疫响应在RA中被认为是抗炎的，但是尚不清楚ILC2是否 在RA中仅发挥疾病保护作用。这笔赠款的目的是收集试点证据表明ILC2 通过分泌表皮生长因子（EGF） - 类似分子，在RA中起致病作用 两极蛋白（AREG）。 ILC2是秘密的AREG，通常有助于维持组织完整性 对感染的反应，但在慢性的背景下，器官纤维化的发病机理也暗示 炎。我们发现，在关节小鼠的关节和 有初步证据表明AREG促进关节炎的严重程度和类似成纤维细胞样的侵略性行为 体外滑膜细胞（FLS）。因此，我们假设联合定位的ILC2促进了RA的疾病活性 通过与AREG的生产与FL的相互作用。该赠款申请建议实验旨在 获得严格的证据表明，ILC2通过AREG的生产来增强小鼠的关节炎的发育（AIM 1），AREG在体外和体内促进了FLS的侵略性和关节破坏行为（AIM 2）。 项目非常适合R21格式，因为目的是收集飞行员证据以支持一个概念 但是，目前被认为是高风险，可能具有违反直觉 通过干扰ILC2-AREG-FLS轴的新型治疗方法。 。