Macrophage Heterogeneity in Rheumatoid Arthritis

类风湿关节炎中的巨噬细胞异质性

• 批准号: 10392246
• 负责人: Harris R Perlman
• 金额: $ 69.46万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392246
• 关键词: ATAC-seq; Adopted; Adoption; Arthritis; Biopsy; Bone Marrow; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chimera organism; Clinical; Data; Development; Dichloromethylene Diphosphonate; Disease; Environment; Enzymes; Exhibits; Exposure to; Future; Gene Expression Profile; Genetic; Genomic approach; Genomics; Growth; Health; Heterogeneity; Homeostasis; Immune; Immunologics; Impairment; Infiltration; Inflammation; Inflammatory; Inflammatory Arthritis; Joints; Knock-out; Knowledge; Label; Lead; Liposomes; Maintenance; Modeling; Molecular; Mus; PTPRC gene; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Population; Production; Recurrence; Recurrent disease; Residencies; Resolution; Response to stimulus physiology; Rheumatoid Arthritis; Role; Sampling; Serum; Severities; Surface; Synovial Cell; Synovial Membrane; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcriptional Regulation; Visit; Work; cell type; combinatorial; cytokine; epigenomics; follow-up; functional genomics; genomic profiles; immune function; interstitial; joint inflammation; joint injury; macrophage; minimally invasive; monocyte; mouse model; prevent; programs; recruit; side effect; single-cell RNA sequencing; targeted treatment; therapeutically effective; transcription factor; treatment response; ultrasound

Project Summary Macrophages are critical to the pathogenesis of rheumatoid arthritis (RA), but several distinct macrophage subpopulations co-exist in the synovium of joints. In steady-state, tissue-resident macrophages contribute to joint integrity and are required for tissue homeostasis. While increased numbers of macrophages during the development of arthritis is associated with inflammation and joint damage, depletion of all macrophages delays resolution in a mouse model of arthritis. Thus, broad targeting of macrophages is unlikely to provide an effective therapeutic option for rheumatoid arthritis. Instead, we propose to characterize the function of synovial macrophage subpopulations in healthy and inflamed joint to determine how they contribute to the pathogenesis of arthritis. We and others have identified at least 4 synovial macrophage subpopulations that differ in their ontogeny and localization within the joint: tissue-resident synovial lining macrophages, tissue- resident interstitial macrophages, monocyte-derived interstitial macrophages, and infiltrating macrophages. However, we currently lack specific targets to regulate macrophage function at the molecular level in the context of developing and relapsing disease. Our prior work demonstrated that macrophage plasticity arises from the combinatorial action of cell-type-specific and environmentally driven transcription factors (TFs) which poise the epigenomic landscape for future stimulus response. Accordingly, our preliminary data confirms that murine synovial macrophage subpopulations exhibit distinct transcriptional profiles associated with different TFs at steady-state, display varying functions in a mouse model of inflammatory arthritis, and can be identified among synovial cells in patients with active RA. We hypothesize that monocyte-macrophage transition is critical for promoting joint inflammation whereas the adoption of the tissue-resident phenotype is required to maintain homeostasis. To test this hypothesis, we will use a combination of genomics approaches with lineage- tracing, bone marrow chimeras, and genetic mouse models as well as clinical samples. In Aim 1, we will murine models to determine the role of monocyte-macrophage transition in promoting joint inflammation. We will compare the transition over time in the steady-state joint to the infiltration of inflammatory macrophages in the serum transfer induced arthritis (STIA) model. In Aim 2, we will determine how the maintenance of the tissue- resident phenotype contributes to joint health using an initial and second challenge model of STIA. We will assess macrophage heterogeneity in the inflamed joint, the role of specific tissue-resident subpopulations, and molecular drivers of the tissue-residency. In Aim 3, we will use single-cell approaches on synovial tissue biopsies to determine whether the composition and transcriptional profile of macrophage subpopulations are associated with response to treatment in RA patients. Together, these aims will clarify the role of different synovial macrophage subpopulations in RA. These results will be critical to the development of targeted therapeutic interventions for RA patients.

项目摘要 巨噬细胞对于类风湿关节炎（RA）的发病机理至关重要，但是几种不同的巨噬细胞 亚群在关节滑膜中共存。在稳态中，组织居民巨噬细胞有助于关节 完整性，是组织稳态所必需的。而巨噬细胞数量增加 关节炎的发展与炎症和关节损伤，所有巨噬细胞延迟的耗尽有关 小鼠关节炎模型中的分辨率。因此，巨噬细胞的广泛靶向不可能提供有效的 类风湿关节炎的治疗选择。相反，我们建议表征滑膜的功能 健康和发炎的关节中的巨噬细胞亚群，以确定它们如何贡献 关节炎的发病机理。我们和其他人已经确定了至少4个滑膜巨噬细胞亚群 关节内的个体发育和定位不同：组织居民滑膜巨噬细胞，组织 - 驻留的间质巨噬细胞，单核细胞衍生的间质巨噬细胞和浸润巨噬细胞。 但是，我们目前缺乏特定的目标来调节分子水平的巨噬细胞功能 发展和复发疾病。我们先前的工作表明，巨噬细胞可塑性是由 细胞类型特异性和环境驱动的转录因子（TFS）的组合作用，使得 表观基因组景观，用于未来的刺激反应。因此，我们的初步数据证实了鼠 滑膜巨噬细胞亚群显示出与不同TF相关的不同转录曲线 稳态，在炎症性关节炎的小鼠模型中显示不同的功能，可以在 活性RA患者的滑细胞。我们假设单核细胞巨噬细胞转变至关重要 为了促进关节炎症，需要采用组织居民表型 保持体内平衡。为了检验这一假设，我们将使用基因组学方法的组合与谱系 - 跟踪，骨髓嵌合体和遗传小鼠模型以及临床样品。在AIM 1中，我们会鼠 确定单核细胞巨噬细胞转变在促进关节炎症中的作用的模型。我们将 比较稳态关节中随时间的过渡与炎症巨噬细胞的渗透 血清转移引起关节炎（Stia）模型。在AIM 2中，我们将确定组织的维持如何 居民表型使用Stia的初始和第二个挑战模型有助于联合健康。我们将评估 发炎关节中的巨噬细胞异质性，特定组织居民亚群的作用和 组织居住的分子驱动因素。在AIM 3中，我们将在滑膜组织活检中使用单细胞方法 确定巨噬细胞亚群的组成和转录轮廓是否相关 RA患者对治疗的反应。这些目标在一起将阐明不同滑膜的作用 RA中的巨噬细胞亚群。这些结果对于靶向治疗的发展至关重要 RA患者的干预措施。