AUTHOR=Waterborg Claire E. J. , Beermann Silke , Broeren Mathijs G. A. , Bennink Miranda B. , Koenders Marije I. , van Lent Peter L. E. M. , van den Berg Wim B. , van der Kraan Peter M. , van de Loo Fons A. J. 

TITLE=Protective Role of the MER Tyrosine Kinase via Efferocytosis in Rheumatoid Arthritis Models

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00742

DOI=10.3389/fimmu.2018.00742

ISSN=1664-3224

ABSTRACT=<sec id="ST1"><title>Objective</title><p>Rheumatoid arthritis (RA) is a chronic and progressive joint disease. It appears that anti-inflammatory feedback mechanisms that could restrain joint inflammation and restore homeostasis are insufficient to perform this control. In this study, we investigated the contribution of the MER tyrosine kinase-mediated anti-inflammatory response on arthritis and whether targeting MER could be a valid approach to treat RA.</p></sec><sec id="ST2"><title>Methods</title><p>KRN serum transfer arthritis (KRN STA) was induced in either <italic>Mertk</italic>-deficient mice or in mice that adenovirally overexpressed <italic>Pros1</italic>. Human synovial micromasses were treated with MER-specific antibodies or PROS1. Collagen-induced arthritis (CIA) mice were treated with MER-specific agonistic antibodies or by viral overexpression of <italic>Pros1</italic>.</p></sec><sec id="ST3"><title>Results</title><p><italic>Mertk<sup>−/−</sup></italic> mice showed exacerbated arthritis pathology, whereas <italic>Pros1</italic> overexpression diminished joint pathology in KRN STA. Human synovial micromasses challenged with MER-specific antibodies enhanced the secretion of inflammatory cytokines, whereas stimulating MER with PROS1 reduced the secretion of these cytokines, confirming the protective role of MER. Next, we treated CIA mice with MER-specific agonistic antibodies, and this unexpectedly resulted in exacerbated arthritis pathology. This was associated with increased numbers of apoptotic cells in their knee joints and higher serum levels of interleukin (IL)-16C, a cytokine released by secondary necrotic neutrophils. Apoptotic cell numbers and IL-16C levels were enhanced during arthritis in <italic>Mertk<sup>−/−</sup></italic> mice and reduced in <italic>Pros1</italic>-overexpressing mice.</p></sec><sec id="ST4"><title>Conclusion</title><p>MER plays a protective role during joint inflammation and activating MER by its ligand PROS1 ameliorates disease. Treatment of mice with MER receptor agonistic antibodies is deleterious due to its counterproductive effect of blocking efferocytosis in the arthritic joint.</p></sec>