Background/Purpose:

Emerging evidence highlighted the role of Tyro3, Axl and Mer Tyrosine Kinase receptors (TAMs) and their ligands Gas6 and ProteinS in the pathogenesis of autoimmunity; however, little is known about their expression and function in Rheumatoid Arthritis (RA). Axl is able to inhibit the pro-inflammatory cascade in Antigen-Presenting-Cells. Its soluble form (sAxl) behaves as a potent decoy receptor for the ligand Gas6, thus playing an essential role in regulating TAMs functions. Given the crucial role of Axl receptor and its ligand Gas6 in controlling inflammation, we aimed to characterise their expression and function in RA.

Methods:

Biologic samples were collected from patients with early inflammatory arthritis (disease duration <12 months) DMARDs and steroids-naïve; all patients underwent an US-guided synovial biopsy of the most inflamed accessible joint before starting treatment. Only patients diagnosed with RA according to ACR/EULAR 2010 criteria were included in this study. Axl/Gas6 expression was evaluated: i) in synovial tissue at gene expression level by next generation sequencing (81 patients); ii) in synovial tissue at protein level through immunohistochemistry (30 patients); iii) in synovial fluid by ELISA (18 patients); iv) in supernatants of RA-fibroblasts-like-cells (FLS) by ELISA.

Results:

Axl mRNA levels, but not GAS6, were significantly down regulated in highly inflamed synovial tissues containing B/T cells ectopic structures compared to non-lymphoid synovitis (p<0.001) and negatively correlated with the synovitis score (r -0.48). Axl gene expression showed a significant strong negative correlation with indexes of disease activity, including ESR, CRP, swollen joint count and DAS28. At protein level, Axl was predominantly detected in cells forming the lining layer or in close association with blood vessels, independently of the synovial pathotype. In RA synovial fluids, sAxl was significantly more abundant in patients characterised by high-inflamed lymphoid synovitis compared to non-lymphoid (28.55 ± 12.99 ng/ml versus 4.86 ± 2.18 ng/ml, p<0.05); moreover, synovial fluid levels of sAxl positively correlated with the synovitis score (r 0.55) and with systemic inflammation (sAxl/ESR r 0.56). In an in vitro system of cultured RA FLS, sAxl shedding and release in the supernatant was significantly increased upon treatment with TNFα in comparison with untreated synovial fibroblasts.

Conclusion:

Axl is down regulated in highly inflamed RA synovial tissues and negatively correlates with multiple markers of disease activity. It can be shed and released into the synovial fluid and its levels are higher in presence of high-inflamed synovitis and positively correlate with systemic inflammation. TNFα is able to enhance Axl proteolytic cleavage from RA synovial fibroblasts. In conclusion, the dysregulation of the TAM system could provide a novel mechanistic explanation of the persistent inflammation characterizing the RA joints but could also be potentially exploited for therapeutic strategies in order to regain tissue homeostasis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tyrosine-kinase-receptor-axl-is-down-regulated-in-highly-inflamed-rheumatoid-synovium-and-negatively-correlates-with-markers-of-disease-activity/