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Updated: Sep 10, 2025
Author Spotlight: Isolation and Culture of Primary Synovial Macrophages and Fibroblasts from Murine Arthritis Tissue
Published on: February 24, 2023
Spatial mapping of rheumatoid arthritis synovial niches reveals a LYVE1+ macrophage network associated with response
Julien De Lima1, Marie-Astrid Boutet2, Olivier Bortolotti3
1Nantes Université, ONIRIS, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, Nantes, France.
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 LYVE1+CD206+tissue-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.
Insights
Restoration of a specific macrophage network in the synovium is key to rheumatoid arthritis (RA) remission with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). This finding reveals new therapeutic targets for RA treatment.
Area of Science:
- Immunology
- Rheumatology
- Cell Biology
Background:
- Rheumatoid arthritis (RA) treatment advances still leave many patients without adequate remission.
- The synovial tissue's cellular dynamics during effective RA treatment are not well understood.
- Identifying these dynamics is crucial for developing improved therapeutic strategies.
Purpose of the Study:
- To map the synovial landscape in RA patients undergoing effective treatment.
- To identify key cellular networks and molecular pathways linked to clinical remission.
- To understand the spatial and dynamic changes in the synovium during RA therapy.
Main Methods:
- High-dimensional imaging mass cytometry on synovial tissues from healthy controls, osteoarthritis, and early RA patients.
- Longitudinal analysis before and after 6 months of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) therapy.
- Validation via RNA-sequencing, immunofluorescence, ligand-receptor analyses, and in vitro coculture assays.
Main Results:
- A LYVE1+CD206+ tissue-resident macrophage network in perivascular niches was identified.
- This network, disrupted in active RA, was restored in patients responding to csDMARDs.
- Restoration correlated with re-established cell interactions and specific molecular pathways (chemokines, annexins, TAM receptors), with LYVE1+ macrophages showing an anti-inflammatory phenotype.
Conclusions:
- The study presents a spatial and dynamic map of the RA synovium's response to therapy.
- The LYVE1+ macrophage network is crucial for synovial homeostasis and its restoration signifies clinical remission.
- These findings highlight novel cellular and molecular targets for more effective RA therapies.
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