Abstract
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 (MerTKposTREM2high and MerTKposLYVE1pos) 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 MerTKpos STMs in remission was
associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations
could therefore be a potential treatment strategy for RA.
Lingua originale | English |
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pagine (da-a) | N/A-N/A |
Rivista | Nature Medicine |
DOI | |
Stato di pubblicazione | Pubblicato - 2020 |
Keywords
- Synovial tissue