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

Alessandra Nerviani, Marie-Astrid Boutet, Giulia Maria Ghirardi, Katriona Goldmann, Elisabetta Sciacca, Felice Rivellese, Elena Pontarini, Edoardo Prediletto, Federico Abatecola, Mattia Caliste, Sara Pagani, Daniele Mauro, Mattia Bellan, Cankut Cubuk, Rachel Lau, Sarah E. Church, Briana M. Hudson, Frances Humby, Michele Bombardieri, Myles J. Lewis and Costantino Pitzalis ()
Additional contact information
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
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46564-6

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