Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis

被引:454
作者
Alivernini, Stefano [1 ,2 ,3 ,4 ]
MacDonald, Lucy [1 ,4 ]
Elmesmari, Aziza [1 ,4 ]
Finlay, Samuel [1 ,4 ]
Tolusso, Barbara [2 ]
Gigante, Maria Rita [2 ]
Petricca, Luca [2 ]
Di Mario, Clara [3 ]
Bui, Laura [5 ]
Perniola, Simone [3 ]
Attar, Moustafa [6 ]
Gessi, Marco [5 ]
Fedele, Anna Laura [2 ]
Chilaka, Sabarinadh [4 ]
Somma, Domenico [4 ]
Sansom, Stephen N. [1 ,6 ]
Filer, Andrew [1 ,7 ,8 ]
McSharry, Charles [4 ]
Millar, Neal L. [4 ]
Kirschner, Kristina [9 ]
Nerviani, Alessandra [10 ]
Lewis, Myles J. [10 ]
Pitzalis, Costantino [10 ]
Clark, Andrew R. [1 ,7 ]
Ferraccioli, Gianfranco [3 ]
Udalova, Irina [1 ,6 ]
Buckley, Christopher D. [1 ,6 ,7 ,8 ]
Gremese, Elisa [1 ,2 ,3 ]
McInnes, Iain B. [1 ,4 ]
Otto, Thomas D. [1 ,4 ]
Kurowska-Stolarska, Mariola [1 ,4 ]
机构
[1] Res Inflammatory Arthrit Ctr Versus Arthrit RACE, Rome, Italy
[2] Fdn Policlin Univ A Gemelli IRCCS, Div Rheumatol, Rome, Italy
[3] Univ Cattolica Sacro Cuore, Inst Rheumatol, Rome, Italy
[4] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland
[5] Fdn Policlin Univ A Gemelli IRCCS, Div Pathol, Rome, Italy
[6] Univ Oxford, Kennedy Inst Rheumatol, Oxford, England
[7] Univ Birmingham, Inst Inflammat & Ageing, Birmingham, W Midlands, England
[8] Univ Birmingham, Univ Hosp Birmingham NHS Fdn Trust, NIHR Birmingham Biomed Res Ctr, Birmingham, W Midlands, England
[9] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland
[10] Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
RESIDENT MACROPHAGES; HETEROGENEITY;
D O I
10.1038/s41591-020-0939-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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(pos)TREM2(high)and MerTK(pos)LYVE1(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. Multiple subpopulations of synovial tissue macrophages with varied transcriptional, phenotypic and functional features may contribute to disease flare and tissue repair in patients with active rheumatoid arthritis and patients in clinical remission.
引用
收藏
页码:1295 / +
页数:30
相关论文
共 60 条
[1]   Phagocytosis imprints heterogeneity in tissue-resident macrophages [J].
A-Gonzalez, Noelia ;
Quintana, Juan A. ;
Garcia-Silva, Susana ;
Mazariegos, Marina ;
Gonzalez de la Aleja, Arturo ;
Nicolas-Avila, Jose A. ;
Walter, Wencke ;
Adrover, Jose M. ;
Crainiciuc, Georgiana ;
Kuchroo, Vijay K. ;
Rothlin, Carla V. ;
Peinado, Hector ;
Castrillo, Antonio ;
Ricote, Mercedes ;
Hidalgo, Andres .
JOURNAL OF EXPERIMENTAL MEDICINE, 2017, 214 (05) :1281-1296
[2]   Synovial Predictors of Differentiation to Definite Arthritis in Patients With Seronegative Undifferentiated Peripheral Inflammatory Arthritis: microRNA Signature, Histological, and Ultrasound Features [J].
Alivernini, Stefano ;
Tolusso, Barbara ;
Petricca, Luca ;
Bui, Laura ;
Di Mario, Clara ;
Gigante, Maria R. ;
Di Sante, Gabriele ;
Benvenuto, Roberta ;
Fedele, Anna L. ;
Federico, Francesco ;
Ferraccioli, Gianfranco ;
Gremese, Elisa .
FRONTIERS IN MEDICINE, 2018, 5
[3]   Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission? [J].
Alivernini, Stefano ;
Tolusso, Barbara ;
Petricca, Luca ;
Bui, Laura ;
Di Sante, Gabriele ;
Peluso, Giusy ;
Benvenuto, Roberta ;
Fedele, Anna Laura ;
Federico, Franco ;
Ferraccioli, Gianfranco ;
Gremese, Elisa .
ANNALS OF THE RHEUMATIC DISEASES, 2017, 76 (07) :1228-1236
[4]   MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis [J].
Alivernini, Stefano ;
Kurowska-Stolarska, Mariola ;
Tolusso, Barbara ;
Benvenuto, Roberta ;
Elmesmari, Aziza ;
Canestri, Silvia ;
Petricca, Luca ;
Mangoni, Antonella ;
Fedele, Anna Laura ;
Di Mario, Clara ;
Gigante, Maria Rita ;
Gremese, Elisa ;
McInnes, Iain B. ;
Ferraccioli, Gianfranco .
NATURE COMMUNICATIONS, 2016, 7
[5]   Tapering and discontinuation of TNF-α blockers without disease relapse using ultrasonography as a tool to identify patients with rheumatoid arthritis in clinical and histological remission [J].
Alivernini, Stefano ;
Peluso, Giusy ;
Fedele, Anna Laura ;
Tolusso, Barbara ;
Gremese, Elisa ;
Ferraccioli, Gianfranco .
ARTHRITIS RESEARCH & THERAPY, 2016, 18
[6]   Developing a Construct to Evaluate Flares in Rheumatoid Arthritis: A Conceptual Report of the OMERACT RA Flare Definition Working Group [J].
Alten, Rieke ;
Pohl, Christof ;
Choy, Ernest H. ;
Christensen, Robin ;
Furst, Daniel E. ;
Hewlett, Sarah E. ;
Leong, Amye ;
May, James E. ;
Sanderson, Tessa C. ;
Strand, Vibeke ;
Woodworth, Thasia G. ;
Bingham, Clifton O., III .
JOURNAL OF RHEUMATOLOGY, 2011, 38 (08) :1745-1750
[7]   Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study [J].
Baker, Kenneth F. ;
Skelton, Andrew J. ;
Lendrem, Dennis W. ;
Scadeng, Adam ;
Thompson, Ben ;
Pratt, Arthur G. ;
Isaacs, John D. .
JOURNAL OF AUTOIMMUNITY, 2019, 105
[8]   Does immunological remission, defined as disappearance of autoantibodies, occur with current treatment strategies? A long-term follow-up study in rheumatoid arthritis patients who achieved sustained DMARD-free status [J].
Boeters, Debbie M. ;
Burgers, Leonie E. ;
Toes, Rene E. M. ;
van der Helm-van Mil, Annette .
ANNALS OF THE RHEUMATIC DISEASES, 2019, 78 (11) :1497-1504
[9]   The orphan nuclear receptor NR4A3 controls the differentiation of monocyte-derived dendritic cells following microbial stimulation [J].
Boulet, Salix ;
Daudelin, Jean-Francois ;
Odagiu, Livia ;
Pelletier, Adam-Nicolas ;
Yun, Tae Jin ;
Lesage, Sylvie ;
Cheong, Cheolho ;
Labrecque, Nathalie .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (30) :15150-15159
[10]   The new ACR/EULAR remission criteria: rationale for developing new criteria for remission [J].
Bykerk, Vivian P. ;
Massarotti, Elena M. .
RHEUMATOLOGY, 2012, 51 :16-20