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

被引：512

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

来源：

NATURE MEDICINE | 2020年 / 26卷 / 08期

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：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

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

页码：1295 / +

页数：30

共 60 条

[11]

Distinct fibroblast subsets drive inflammation and damage in arthritis [J].

Croft, Adam P. ;

Campos, Joana ;

Jansen, Kathrin ;

Turner, Jason D. ;

Marshall, Jennifer ;

Attar, Moustafa ;

Savary, Loriane ;

Wehmeyer, Corinna ;

Naylor, Amy J. ;

Kemble, Samuel ;

Begum, Jenefa ;

Durholz, Kerstin ;

Perlman, Harris ;

Barone, Francesca ;

McGettrick, Helen M. ;

Fearon, Douglas T. ;

Wei, Kevin ;

Raychaudhuri, Soumya ;

Korsunsky, Ilya ;

Brenner, Michael B. ;

Coles, Mark ;

Sansom, Stephen N. ;

Filer, Andrew ;

Buckley, Christopher D. .

NATURE, 2019, 570 (7760) :246-+

[12]

Locally renewing resident synovial macrophages provide a protective barrier for the joint [J].

Culemann, Stephan ;

Grueneboom, Anika ;

Angel Nicolas-Avila, Jose ;

Weidner, Daniela ;

Laemmle, Katrin Franziska ;

Rothe, Tobias ;

Quintana, Juan A. ;

Kirchner, Philipp ;

Krljanac, Branislav ;

Eberhardt, Martin ;

Ferrazzi, Fulvia ;

Kretzschmar, Elke ;

Schicht, Martin ;

Fischer, Kim ;

Gelse, Kolja ;

Faas, Maria ;

Pfeifle, Rene ;

Ackermann, Jochen A. ;

Pachowsky, Milena ;

Renner, Nina ;

Simon, David ;

Haseloff, Reiner F. ;

Ekici, Arif B. ;

Baeuerle, Tobias ;

Blasig, Ingolf E. ;

Vera, Julio ;

Voehringer, David ;

Kleyer, Arnd ;

Paulsen, Friedrich ;

Schett, Georg ;

Hidalgo, Andres ;

Kroenke, Gerhard .

NATURE, 2019, 572 (7771) :670-+

[13]

Tissue-resident macrophages [J].

Davies, Luke C. ;

Jenkins, Stephen J. ;

Allen, Judith E. ;

Taylor, Philip R. .

NATURE IMMUNOLOGY, 2013, 14 (10) :986-995

[14]

MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data [J].

Finak, Greg ;

McDavid, Andrew ;

Yajima, Masanao ;

Deng, Jingyuan ;

Gersuk, Vivian ;

Shalek, Alex K. ;

Slichter, Chloe K. ;

Miller, Hannah W. ;

McElrath, M. Juliana ;

Prlic, Martin ;

Linsley, Peter S. ;

Gottardo, Raphael .

GENOME BIOLOGY, 2015, 16

[15]

Firestein G.S., 2016, KELLEY FIRESTEINS TX, VVolume 1

[16]

Immunopathogenesis of Rheumatoid Arthritis [J].

Firestein, Gary S. ;

McInnes, Iain B. .

IMMUNITY, 2017, 46 (02) :183-196

[17]

Cytokine release in patients with CLL treated with obinutuzumab and possible relationship with infusion-related reactions [J].

Freeman, Ciara L. ;

Morschhauser, Franck ;

Sehn, Laurie ;

Dixon, Mark ;

Houghton, Richard ;

Lamy, Thierry ;

Fingerle-Rowson, Guenter ;

Wassner-Fritsch, Elisabeth ;

Gribben, John G. ;

Hallek, Michael ;

Salles, Gilles ;

Cartron, Guillaume .

BLOOD, 2015, 126 (24) :2646-2649

[18]

Ultrasound assessment as predictor of disease relapse in children and adults with arthritis in clinical stable remission: new findings but still unmet needs [J].

Gremese, Elisa ;

Fedele, Anna Laura ;

Alivernini, Stefano ;

Ferraccioli, Gianfranco .

ANNALS OF THE RHEUMATIC DISEASES, 2018, 77 (10) :1391-1393

[19]

NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis [J].

Hanna, Richard N. ;

Shaked, Iftach ;

Hubbeling, Harper G. ;

Punt, Jennifer A. ;

Wu, Runpei ;

Herrley, Erica ;

Zaugg, Claudia ;

Pei, Hong ;

Geissmann, Frederic ;

Ley, Klaus ;

Hedrick, Catherine C. .

CIRCULATION RESEARCH, 2012, 110 (03) :416-U127

[20]

Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab [J].

Herenius, M. M. J. ;

Thurlings, R. M. ;

Wijbrandts, C. A. ;

Bennink, R. J. ;

Dohmen, S. E. ;

Voermans, C. ;

Wouters, D. ;

Izmailova, E. S. ;

Gerlag, D. M. ;

van Eck-Smit, B. L. F. ;

Tak, P. P. .

ANNALS OF THE RHEUMATIC DISEASES, 2011, 70 (06) :1160-1162

← 1 2 3 4 5 6 →