Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTK^posTREM2^high and MerTK^posLYVE1^pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK^pos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK^pos STM subpopulations could therefore be a potential treatment strategy for RA.

类风湿关节炎（RA）无药缓解的免疫调节机制尚不清楚。我们假设缓解期持续存在的滑膜组织巨噬细胞（STM）有助于关节稳态。我们使用单细胞转录组学分析了 32,000 个 STM，并确定了早期/活动性 RA、难治性/活动性 RA 和持续缓解期 RA 患者的表型变化。每种临床状态的特征是四个不同的 STM 亚群中九个离散表型簇的不同频率，具有不同的稳态、调节和炎症功能。该细胞图谱与滑膜活检荧光激活细胞分选 STM 的深层表型、空间和功能分析相结合，揭示了两个 STM 亚群（MerTK ^pos TREM2 ^high和 MerTK ^pos LYVE1 ^pos），具有独特的缓解转录组特征，富含炎症负调节因子。这些 STM 是消炎脂质介质的有效产生者，并在体外诱导滑膜成纤维细胞的修复反应。^{缓解期 MerTK pos} STM比例较低与治疗停止后疾病复发风险增加相关。因此， MerTK ^pos STM 亚群的治疗调节可能是 RA 的潜在治疗策略。