类风湿性关节炎滑膜微环境的空间图谱揭示了与治疗反应相关的LYVE1巨噬细胞网络。
Spatial mapping of rheumatoid arthritis synovial niches reveals a LYVE1 macrophage network associated with response to therapy.
作者信息
De Lima Julien, Boutet Marie-Astrid, Bortolotti Olivier, Chépeaux Laure-Agnès, Glasson Yaël, Dumé Anne-Sophie, Lau Rachel, Humbert Paul, Allain Sophie, Le Pluart Adrien, Nerviani Alessandra, Fossati-Jimack Liliane, Michaud Henri-Alexandre, Guicheux Jérôme, Le Goff Benoit, Lewis Myles J, Pitzalis Costantino, Courties Gabriel, Apparailly Florence, Blanchard Frederic
机构信息
Nantes Université, ONIRIS, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, Nantes, France.
Nantes Université, ONIRIS, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, Nantes, France; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
出版信息
Ann Rheum Dis. 2025 Aug 22. doi: 10.1016/j.ard.2025.07.019.
OBJECTIVES
Despite advances in rheumatoid arthritis (RA) treatment, a significant proportion of patients fail to achieve adequate remission. The dynamic cellular and architectural changes within the synovium that underpin therapeutic success remain poorly understood. This study aimed to unravel the synovial landscape during effective RA treatment, identifying key cellular networks and molecular pathways associated with remission.
METHODS
We performed high-dimensional imaging mass cytometry on synovial tissues from healthy controls, patients with osteoarthritis, and patients with early RA longitudinally before and after 6 months of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) therapy. Findings were validated using whole-tissue RNA-sequencing and immunofluorescence in larger patient cohorts, and integrated with ligand-receptor analyses from public single-cell RNA-seq datasets and in vitro functional coculture assays.
RESULTS
Our deep spatial profiling pinpointed a critical LYVE1CD206tissue-resident macrophage network, localised within perivascular niches alongside fibroblasts and vascular cells. This homeostatic network was disrupted in active RA but restored in patients responding well to csDMARDs. This restoration correlated with the re-establishment of specific cell-cell interactions and was governed by distinct molecular pathways, including chemokines, annexins, and TAM (TYRO3, AXL, MERTK) receptors. Functionally, LYVE1 macrophages demonstrated a regulatory, anti-inflammatory phenotype in vitro, contrasting with proinflammatory myeloid cells.
CONCLUSIONS
This study provides an unprecedented spatial and dynamic blueprint of the RA synovium's response to therapy. We identify the LYVE1 macrophage network as a pivotal component of synovial homeostasis and its restoration as a hallmark of clinical remission. These findings unveil novel cellular and molecular targets, paving the way for more active therapeutic strategies.
目的
尽管类风湿关节炎（RA）治疗取得了进展，但仍有相当一部分患者未能实现充分缓解。滑膜内动态的细胞和结构变化是治疗成功的基础，但目前仍知之甚少。本研究旨在揭示有效RA治疗期间的滑膜情况，确定与缓解相关的关键细胞网络和分子途径。
方法
我们对健康对照、骨关节炎患者和早期RA患者的滑膜组织进行了高维成像质谱流式细胞术分析，这些患者在接受传统合成改善病情抗风湿药物（csDMARD）治疗6个月前后进行了纵向观察。研究结果在更大的患者队列中通过全组织RNA测序和免疫荧光进行了验证，并与来自公共单细胞RNA测序数据集的配体-受体分析以及体外功能共培养试验相结合。
结果
我们的深度空间分析确定了一个关键的LYVE1⁺CD206⁺组织驻留巨噬细胞网络，其位于血管周围龛内，与成纤维细胞和血管细胞相邻。这个稳态网络在活动性RA中被破坏，但在对csDMARDs反应良好的患者中得以恢复。这种恢复与特定细胞间相互作用的重新建立相关，并受不同分子途径的调控，包括趋化因子、膜联蛋白和TAM（TYRO3、AXL、MERTK）受体。在功能上，LYVE1巨噬细胞在体外表现出调节性、抗炎表型，与促炎性髓样细胞形成对比。
结论
本研究提供了RA滑膜对治疗反应的前所未有的空间和动态蓝图。我们确定LYVE1巨噬细胞网络是滑膜稳态的关键组成部分，其恢复是临床缓解的标志。这些发现揭示了新的细胞和分子靶点，为更积极的治疗策略铺平了道路。
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