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

Author

Listed:
  • Alessandra Nerviani

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Marie-Astrid Boutet

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust
    UMR 1229)

  • Giulia Maria Ghirardi

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Katriona Goldmann

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Elisabetta Sciacca

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Felice Rivellese

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Elena Pontarini

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Edoardo Prediletto

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Federico Abatecola

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Mattia Caliste

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Sara Pagani

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Daniele Mauro

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Mattia Bellan

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust
    University of Eastern Piedmont and Maggiore della Carita Hospital)

  • Cankut Cubuk

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Rachel Lau

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Sarah E. Church

    (NanoString Technologies Inc)

  • Briana M. Hudson

    (NanoString Technologies Inc)

  • Frances Humby

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Michele Bombardieri

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Myles J. Lewis

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust)

  • Costantino Pitzalis

    (Queen Mary University of London & NIHR BRC Barts Health NHS Trust
    Humanitas University & IRCCS Humanitas Research Hospital)

Abstract

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.

Suggested Citation

  • Alessandra Nerviani & Marie-Astrid Boutet & Giulia Maria Ghirardi & Katriona Goldmann & Elisabetta Sciacca & Felice Rivellese & Elena Pontarini & Edoardo Prediletto & Federico Abatecola & Mattia Calis, 2024. "Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46564-6
    DOI: 10.1038/s41467-024-46564-6
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    References listed on IDEAS

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