Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis
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 phen...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| 格式: | Journal article |
| 語言: | English |
| 出版: |
Nature Research
2020
|
| _version_ | 1826293877657567232 |
|---|---|
| author | Alivernini, S MacDonald, L Elmesmari, A Finlay, S Tolusso, B Gigante, MR Petricca, L Di Mario, C Bui, L Perniola, S Attar, M Gessi, M Fedele, AL Chilaka, S Somma, D Sansom, SN Filer, A McSharry, C Millar, NL Kirschner, K Nerviani, A Lewis, MJ Pitzalis, C Clark, AR Ferraccioli, G Udalova, I Buckley, CD Gremese, E McInnes, IB Otto, TD Kurowska-Stolarska, M |
| author_facet | Alivernini, S MacDonald, L Elmesmari, A Finlay, S Tolusso, B Gigante, MR Petricca, L Di Mario, C Bui, L Perniola, S Attar, M Gessi, M Fedele, AL Chilaka, S Somma, D Sansom, SN Filer, A McSharry, C Millar, NL Kirschner, K Nerviani, A Lewis, MJ Pitzalis, C Clark, AR Ferraccioli, G Udalova, I Buckley, CD Gremese, E McInnes, IB Otto, TD Kurowska-Stolarska, M |
| author_sort | Alivernini, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T03:36:56Z |
| format | Journal article |
| id | oxford-uuid:bc9e134b-72ea-4cb5-abb7-0cb30d89916e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:36:56Z |
| publishDate | 2020 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:bc9e134b-72ea-4cb5-abb7-0cb30d89916e2022-03-27T05:25:51ZDistinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bc9e134b-72ea-4cb5-abb7-0cb30d89916eEnglishSymplectic ElementsNature Research2020Alivernini, SMacDonald, LElmesmari, AFinlay, STolusso, BGigante, MRPetricca, LDi Mario, CBui, LPerniola, SAttar, MGessi, MFedele, ALChilaka, SSomma, DSansom, SNFiler, AMcSharry, CMillar, NLKirschner, KNerviani, ALewis, MJPitzalis, CClark, ARFerraccioli, GUdalova, IBuckley, CDGremese, EMcInnes, IBOtto, TDKurowska-Stolarska, MImmune-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. |
| spellingShingle | Alivernini, S MacDonald, L Elmesmari, A Finlay, S Tolusso, B Gigante, MR Petricca, L Di Mario, C Bui, L Perniola, S Attar, M Gessi, M Fedele, AL Chilaka, S Somma, D Sansom, SN Filer, A McSharry, C Millar, NL Kirschner, K Nerviani, A Lewis, MJ Pitzalis, C Clark, AR Ferraccioli, G Udalova, I Buckley, CD Gremese, E McInnes, IB Otto, TD Kurowska-Stolarska, M Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| title | Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| title_full | Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| title_fullStr | Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| title_full_unstemmed | Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| title_short | Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| title_sort | distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis |
| work_keys_str_mv | AT aliverninis distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT macdonaldl distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT elmesmaria distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT finlays distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT tolussob distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT gigantemr distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT petriccal distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT dimarioc distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT buil distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT perniolas distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT attarm distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT gessim distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT fedeleal distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT chilakas distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT sommad distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT sansomsn distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT filera distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT mcsharryc distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT millarnl distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT kirschnerk distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT nerviania distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT lewismj distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT pitzalisc distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT clarkar distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT ferracciolig distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT udalovai distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT buckleycd distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT gremesee distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT mcinnesib distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT ottotd distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis AT kurowskastolarskam distinctsynovialtissuemacrophagesubsetsregulateinflammationandremissioninrheumatoidarthritis |