Macrophage Heterogeneity in Rheumatoid Arthritis

项目摘要 巨噬细胞在类风湿关节炎(RA)的发病机制中起关键作用，但有几种不同的巨噬细胞 关节滑膜中各亚群共存。在稳定状态下，组织驻留的巨噬细胞有助于关节 完整性，是组织动态平衡所必需的。虽然巨噬细胞的数量在 关节炎的发展与炎症和关节损伤、所有巨噬细胞耗尽的延迟有关 在关节炎小鼠模型中的分辨率。因此，广泛靶向巨噬细胞不太可能提供有效的 类风湿性关节炎的治疗选择。相反，我们建议描述滑膜的功能 巨噬细胞亚群在健康和炎症关节中的作用 关节炎的发病机制。我们和其他人已经确定了至少4个滑膜巨噬细胞亚群 不同的个体发育和关节内的定位：组织驻留的滑膜衬里巨噬细胞，组织- 驻留的间质巨噬细胞、单核细胞来源的间质巨噬细胞和浸润性巨噬细胞。 然而，我们目前缺乏在分子水平上调节巨噬细胞功能的特定靶点。 发展和复发的疾病。我们先前的工作表明，巨噬细胞的可塑性源于 细胞类型特异的转录因子和环境驱动的转录因子(TF)的组合作用 未来刺激反应的表观经济图景。因此，我们的初步数据证实，小鼠 滑膜巨噬细胞亚群表现出与不同转录因子相关的不同转录图谱 稳定状态，在炎症性关节炎的小鼠模型中表现出不同的功能，并可在以下几个方面进行识别 活动期类风湿关节炎患者滑膜细胞的研究我们假设单核细胞-巨噬细胞的转变是至关重要的 用于促进关节炎症，而采用组织驻留表型需要 保持动态平衡。为了验证这一假设，我们将使用基因组学方法和血统相结合的方法- 示踪、骨髓嵌合体、遗传小鼠模型以及临床样本。在目标1中，我们将小鼠 确定单核-巨噬细胞转化在促进关节炎症中的作用的模型。我们会 比较稳定状态关节中随时间的转移与关节内炎性巨噬细胞的渗透 血清转移性关节炎(STIA)模型。在目标2中，我们将确定组织的维护如何- 使用STIA的初始和第二个挑战模型，居民表型对关节健康有贡献。我们将评估 炎症关节中巨噬细胞的异质性，特定组织驻留亚群的作用，以及 组织驻留的分子驱动因素。在目标3中，我们将使用单细胞方法进行滑膜组织活检。 确定巨噬细胞亚群的组成和转录图谱是否相关 对RA患者的治疗有反应。这些目标将共同阐明不同滑膜的作用。 类风湿关节炎患者的巨噬细胞亚群。这些结果将对靶向治疗的发展至关重要。 对类风湿关节炎患者的干预。

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.