Macrophage Heterogeneity in Rheumatoid Arthritis

项目摘要 巨噬细胞在类风湿性关节炎（RA）的发病机制中至关重要，但几种不同的巨噬细胞 亚群共存于关节滑膜中。在稳定状态下，组织驻留的巨噬细胞有助于关节 完整性和组织稳态所需。虽然在生长过程中巨噬细胞的数量增加， 关节炎的发展与炎症和关节损伤有关，所有巨噬细胞的消耗延迟 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免疫抑制剂。 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， 健康和发炎关节中的巨噬细胞亚群，以确定它们如何促进关节炎。 关节炎的发病机制。我们和其他人已经确定了至少4种滑膜巨噬细胞亚群， 不同的个体发育和关节内的定位：组织驻留滑膜衬里巨噬细胞，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性巨噬细胞。 然而，我们目前缺乏具体的目标，以调节巨噬细胞的功能，在分子水平的背景下 发展和复发的疾病。我们先前的工作表明，巨噬细胞的可塑性来自于 细胞类型特异性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基因组景观。因此，我们的初步数据证实， 滑膜巨噬细胞亚群表现出与不同TF相关的不同转录谱， 稳态，在炎性关节炎小鼠模型中显示不同的功能，并且可以在 活动性RA患者的滑膜细胞。我们假设单核细胞-巨噬细胞转化是关键的 而采用组织驻留表型需要 保持体内平衡为了验证这一假设，我们将使用基因组学方法与谱系相结合- 示踪、骨髓嵌合体和遗传小鼠模型以及临床样品。在目标1中， 模型，以确定单核细胞-巨噬细胞转变在促进关节炎症中的作用。我们将 将稳态关节中随时间的转变与关节中炎性巨噬细胞的浸润进行比较， 血清转移诱导的关节炎（STIA）模型。在目标2中，我们将确定如何维持组织- 使用STIA的初始和第二次激发模型，常驻表型有助于关节健康。我们将评估 炎症关节中的巨噬细胞异质性，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，我们将在滑膜组织活检中使用单细胞方法 以确定巨噬细胞亚群的组成和转录谱是否与 对RA患者的治疗有反应。总之，这些目标将阐明不同滑膜的作用， 巨噬细胞亚群。这些结果对于靶向治疗药物的开发具有重要意义。 对RA患者进行干预。

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.