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

Alessandra Nerviani1, Marie-Astrid Boutet1,2, Giulia Maria Ghirardi1

  • 1Centre 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.

Nature Communications
|March 17, 2024
PubMed

Insights

The TAM tyrosine kinases, Axl and MerTK, are key in rheumatoid arthritis (RA). High AXL levels correlate with less inflammation in treatment-naive patients, and their expression changes with disease stage and IL-6 inhibition therapy.

Area of Science:

  • Immunology
  • Rheumatology
  • Molecular Biology

Background:

  • The TAM receptor tyrosine kinases, Axl and MerTK, are implicated in rheumatoid arthritis (RA) pathogenesis.
  • Understanding their role in the synovium is crucial for RA treatment strategies.

Purpose of the Study:

  • To investigate the relationship between Axl and MerTK expression, synovial histopathology, and disease activity in RA patients.
  • To determine the topographical expression and longitudinal modulation of Axl/MerTK by targeted therapies.

Main Methods:

  • Utilized a unique synovial tissue bioresource from RA patients.
  • Employed immunohistochemistry, fluorescence, and digital spatial profiling for topographical analysis.
  • Assessed Axl/MerTK levels in relation to disease activity, histopathology, and gene expression.
  • Investigated the modulation of MerTK shedding by Toll-like receptor 4-stimulated synovial fibroblasts.

Main Results:

  • In treatment-naive RA patients, high AXL levels were associated with pauci-immune histology, low disease activity, and inverse correlation with pro-inflammatory gene expression.
  • Axl was preferentially expressed in the lining layer of the rheumatoid synovium, with its soluble ectodomain linked to histopathology.
  • Toll-like receptor 4 stimulation influenced MerTK shedding by macrophages.
  • Axl/MerTK expression was modulated by disease stage and therapeutic interventions, including IL-6 inhibition.

Conclusions:

  • Axl and MerTK represent a dynamic axis in RA synovium, influenced by cellular features, disease progression, and treatment.
  • Targeting Axl/MerTK may offer novel therapeutic avenues for rheumatoid arthritis.

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