Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis.

Humans Arthritis, Rheumatoid Axl Receptor Tyrosine Kinase c-Mer Tyrosine Kinase / genetics Inflammation / metabolism Interleukin-6 / metabolism Proto-Oncogene Proteins / genetics Receptor Protein-Tyrosine Kinases / genetics Synovial Membrane / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
16 Mar 2024
Historique:
received: 08 03 2023
accepted: 27 02 2024
medline: 18 3 2024
pubmed: 17 3 2024
entrez: 17 3 2024
Statut: epublish

Résumé

The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment.

Identifiants

DOI: 10.1038/s41467-024-46564-6 PMID: 38493215
pubmed: 38493215
doi: 10.1038/s41467-024-46564-6
pii: 10.1038/s41467-024-46564-6
doi:

Substances chimiques

Axl Receptor Tyrosine Kinase 0
c-Mer Tyrosine Kinase EC 2.7.10.1
Interleukin-6 0
Proto-Oncogene Proteins 0
Receptor Protein-Tyrosine Kinases EC 2.7.10.1
IL6 protein, human 0
MERTK protein, human EC 2.7.10.1
AXL protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2398

Subventions

Organisme : RCUK | Medical Research Council (MRC)
ID : G0800648
Organisme : DH | NIHR | Efficacy and Mechanism Evaluation Programme (NIHR Efficacy and Mechanism Evaluation Programme)
ID : 11/100/76
Organisme : DH | National Institute for Health Research (NIHR)
ID : 131575
Organisme : DH | National Institute for Health Research (NIHR)
ID : TRF-2018-11-ST2-002
Organisme : RCUK | MRC | Medical Research Foundation
ID : MR/V012509/1
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : ARF202004011786

Informations de copyright

© 2024. The Author(s).

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Auteurs

Alessandra Nerviani (A)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0003-4064-4014

Marie-Astrid Boutet (MA)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
Nantes Université, Oniris, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France.

Giulia Maria Ghirardi (GM)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0002-4176-2031

Katriona Goldmann (K)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Elisabetta Sciacca (E)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0001-7525-1558

Felice Rivellese (F)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0002-6759-7521

Elena Pontarini (E)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0003-0439-0344

Edoardo Prediletto (E)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0001-6830-0614

Federico Abatecola (F)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0009-0008-2409-1396

Mattia Caliste (M)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Sara Pagani (S)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Daniele Mauro (D)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Mattia Bellan (M)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
Department of Rheumatology, University of Eastern Piedmont and Maggiore della Carita Hospital, Novara, Italy.

Cankut Cubuk (C)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Rachel Lau (R)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0002-8330-8048

Sarah E Church (SE)

NanoString Technologies Inc, Seattle, WA, USA.
ORCID: 0000-0002-7194-4282

Briana M Hudson (BM)

NanoString Technologies Inc, Seattle, WA, USA.

Frances Humby (F)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Michele Bombardieri (M)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.

Myles J Lewis (MJ)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK.
ORCID: 0000-0001-9365-5345

Costantino Pitzalis (C)

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London, UK. c.pitzalis@qmul.ac.uk.
Department of Biomedical Sciences, Humanitas University & IRCCS Humanitas Research Hospital, Milan, Italy. c.pitzalis@qmul.ac.uk.
ORCID: 0000-0003-1326-5051

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Polyarthrite rhumatoïde › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Axl Receptor Tyrosine Kinase › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › c-Mer Tyrosine kinase › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-6 › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs à activité tyrosine kinase › Axl and MerTK regulate synovial inflammation...
questionsmedicales.fr › Appareil locomoteur › Squelette › Articulations › Capsule articulaire › Membrane synoviale › Axl and MerTK regulate synovial inflammation...