Background/Purpose: Rheumatoid arthritis (RA) manifests in a symmetrical fashion in anatomically distinct synovial joints. The innate immune system, which plays a crucial role in the pathogenesis of RA, is regulated by anti-inflammatory feedback mechanisms such as the tyrosine kinase receptor family TYRO3, AXL and MER. Of importance, AXL is mainly expressed on sentinel cells. We investigated the synovial expression of AXL and its putative anti-inflammatory role in a macrophage-dependent model of arthritis.

Methods: Tissue sections of ankle and knee joints of naïve mice were studied for protein expression of AXL. KRN serum transfer arthritis was induced in Axl^-/- and wild-type (WT) mice. Ankle and knee joints were assessed macroscopically and histologically. Naïve WT mice were injected intra-articularly in the knee joint with adenoviruses overexpressing active TGF-β1 or Luciferase. Protein expression of AXL on tissue sections and/or gene expression in synovial biopsies from naïve, arthritic and adenovirus-treated ankle and/or knee joints was examined. Human RA synovium was examined for gene expression. Human monocyte-derived macrophages were treated with recombinant TGF-β1.

Results: When examining naïve murine joints, synovial cells of the ankle joints were AXL positive, but knee joints of the same mice were not, indicating a profound difference between these two weight-bearing joints. To examine whether AXL played a protective role during arthritis, we induced arthritis in Axl^-/- and WT mice. The ankle joints of Axl^-/- mice showed an increased macroscopic disease score during arthritis development (p<0.001 at day 7). In agreement with this, histology of ankle joints showed significantly increased arthritis pathology in Axl^-/- mice. No effect of Axl gene deletion was observed on gonarthritis pathology and the synovial expression of inflammatory genes. To unravel the cause for the noteworthy difference in AXL expression between knee and ankle, we investigated the role of TGF-β, a factor known to induce AXL. As hypothesized, Tgfb1 expression was significantly higher in synovium of ankle compared to synovium of knee joints in naïve mice (p<0.01), which correlated with Axl expression (Pearson r=0.8860, p=0.0012). In addition, adenoviral overexpression of TGFB1 induced AXL expression in synovium of knee joints (p<0.05), a tissue devoid of AXL during homeostasis. The TGF-β1-induced AXL expression appeared to be conserved in humans. We observed a correlation between TGFB1 and AXL expression in human RA synovium (Pearson r=0.7233, p=0.0035) and TGF-β1 stimulation enhanced the expression of AXL in human macrophages (p<0.01).

Conclusion: Our study shows remarkable differences in synovial AXL expression between ankle and knee joints and this is in accordance with the observation that AXL dampens arthritis in ankle but not in knee joints. We provide evidence that these local differences in AXL are due to TGF-β1. It is tempting to speculate that the differences in AXL expression and its innate immune protective effector role could explain the lower arthritis incidence in ankle joints compared to other weight-baring joints in humans (reviewed in DiStefano and Pinney. Semin Arthro. 2010).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tgf-%ce%b21-induces-axl-in-murine-and-human-synovium-and-protects-ankle-joints-but-not-knee-joints-during-murine-inflammatory-arthritis/