Background MerTK is an inhibitory tyrosine kinase receptor activated in several immune cells upon binding of its ligand Growth-Arrest-Specific-6 (Gas6). MerTK/Gas6 axis controls inflammation and immune system in animal models and its loss induces systemic chronic inflammation and autoimmunity. In Rheumatoid Arthritis (RA) patients Gas6 plasmatic level is decreased compared to healthy subjects1 while the over-expression of MerTK agonists in collagen-induced arthritis ameliorates disease2. However, little is known about the MerTK/Gas6 system expression and functional role within the synovial tissue in RA patients.
Objectives To characterize the expression of MerTK/Gas6 in human rheumatoid synovitis, investigating the mechanisms leading to activation/resistance of RA synovial cells to MerTK-mediated regulation of inflammation.
Methods MerTK expression in synovial tissue was assessed by immunohistochemistry/immunofluorescence staining. MerTK/CD163 synovial tissue gene expression was analyzed in 30 early-RA patients treatment-naïve. Mononuclear cells isolated from inflammatory synovial fluids were stimulated with rhGas6 (200 ng/ml) for 24 h and interleukin (IL) 10 production was measured in cells supernatant by ELISA. Synovial fibroblasts isolated from RA synovial tissue were stimulated with Toll-Like-Receptor (TLR) 3 and 4 ligands (respectively polyinosinic-polycytidylic acid and lipopolysaccharide); Gas6 secretion in stimulated and resting fibroblasts was quantified by ELISA at different time points.
Results MerTK was strongly expressed by resident CD68+ synovial macrophages in both the lining and sub-lining; moreover, MerTK-expressing cells were detected within ectopic-lymphoid-structures. MerTK mRNA in treatment-naïve early RA patients was positively correlated with CD163, a marker of anti-inflammatory-polarized-macrophages (r=0.58), but not with CD68. RA synovial fluid lympho-mononuclear cells up-regulated the expression of IL10 in the presence of rhGas6. Finally, RA synovial fibroblasts constitutively released Gas6 but at levels significantly lower compared to RA dermal fibroblast. Moreover, TLR-activation of RA synovial fibroblasts led to a significant decrease in Gas6 expression.
Conclusions The MerTK/Gas6 inhibitory axis is expressed in RA synovitis. In vitro, exogenous Gas6 exerted an immune-modulatory role on synovial fluid mononuclear cells by increasing the release of anti-inflammatory cytokines. Conversely, the diminished availability of Gas6 in synovial stromal cells following pro-inflammatory stimuli may contribute to the chronic inflammation in the rheumatoid synovium. Our data suggest that the exploitation of the anti-inflammatory properties of the Gas6/MerTK axis might constitute a novel therapeutic approach in RA.
Bassyouni IH et al. Diminished soluble levels of growth arrest specific protein 6 and tyrosine kinase receptor Axl in patients with rheumatoid arthritis. Int J Rheum Dis. 2014 Apr
van den Brand BT et al. Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis. Arthritis Rheum. 2013 Mar
Disclosure of Interest None declared