P076 Synovial tissue from rheumatoid arthritis patients shed their anti-inflammatory – and efferocytosis receptor MER
Authors: J Vullings, C Waterborg, M Koenders, P van der Kraan, F van de Loo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> We recently showed that the tyrosine-protein kinase MER, a member of the TAM (TYRO, AXL, MER) receptor family plays a protective role in mouse models of rheumatoid arthritis (RA).<sup>1 2</sup> In both humans and mice, MER can be proteolytically cleaved and this soluble MER (sMER) acts as a decoy receptor for the TAM receptor ligands Growth Arrest-Specific 6 (GAS6) and Protein S. A recent study showed that sMER correlates with disease activity and bone destruction in RA patients.<sup>3</sup> In this study, we measured whether sMER was also increased in the circulation of arthritic mice and in synovial fluid and conditioned medium of synovium explants from RA patients. <h3>Methods</h3> KRN serum transfer arthritis was induced and mice were sacrificed at day 7 of full blown arthritis. Ankle joints were immunostained for MER (n=15) and sMER levels were measured in serum at day 0 and 7 (n=13). Human synovial explants of RA (n=15) and osteoarthritis (OA)(n=17) patients were immunostained for MER. Synovial explants were cultured 24 hours and released sMER and GAS6 was measured by ELISA. The level of sMER, sAXL, GAS6, IL-6, TNFa, IL-1b was measured in synovial fluid of RA (n=21) and OA patients (n=11) by ELISA or multiplex array. <h3>Results</h3> Serum sMER levels were increased in arthritic mice whereas the amount of MER<sup>+</sup> synovial cells was unaltered. In human RA synovium, numerous MER<sup>+</sup> macrophages were present in the lining and sublining. We found significantly enhanced sMER and GAS6 in the synovium culture media (p=0.0045 and 0.0177) and synovial fluid (p=0.0001 and 0.0189) of RA patients as compared to OA patients. Soluble AXL levels in synovial fluid of RA and OA patients was high but did not differ (p=0.5256). In synovial fluid of RA patients, sMER and GAS6 did not correlate with TNFα (Pearson r=0.5587) or IL-1β (Pearson r=−0.1667), and negatively correlated with IL- 6 (Pearson r=−0.9608). <h3>Conclusions</h3> Systemic sMER levels are enhanced in experimental arthritis, in line with the observation of Xu et al in RA patients. Synovial shedding of MER was higher in RA– than in OA patients, but this was not reflected by differences in MER positive synovial cells. As sMER acts as a decoy receptor the anti-inflammatory response might be impaired and hence enhance cytokine release by the synovium, but this was not observed. The level of sMER and sAXL was either not high enough to suppress the innate immune response or efferocytosis did not play a major role in these RA patients with end stage disease. The putative effect of sMER on the adaptive immune response remains to be investigated and this might contribute to the pathogenesis of RA. <h3>References</h3> Waterborg, <i>et al. Frontiers in Immunology</i> 2018. Waterborg, <i>et al. Annals of Rheumatic Diseases</i> 2017. Xu, <i>et al. Clinical &amp; Experimental Immunology</i> 2018. <h3>Disclosure of Interest</h3> None declared.