FRI0037 Mer-mediated efferocytosis tempers arthritis by preventing neutrophils to go into secondary necrosis and spill their inflammatory content in the joint
Authors: CEJ Waterborg, S Beermann, MB Bennink, MI Koenders, PLEM van Lent, F van den Hoogen, PM van der Kraan, FAJ van de Loo
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis is characterized by an inflammatory response in synovial joints, showing a predominant influx of neutrophils. These cells are cytotoxic and contribute to matrix degradation. In addition, they are implicated as a source of citrullinated auto-antigens, leading to the production of anti-citrullinated protein antibodies. Neutrophils have a relative short life span and many of them undergo apoptosis. If they are not cleared, they undergo secondary necrosis and release their cell content. A key mediator in the resolution of inflammation and the uptake of apoptotic cells, or efferocytosis, is the receptor tyrosine kinase Mer. <h3>Objectives</h3> To elucidate the local role of Mer during gonarthritis. <h3>Methods</h3> Macrophages were transduced by adenoviruses encoding the Mer ligand <i>Pros1</i> or <i>Luciferase</i>. One day after the collagen booster injection in mice, Mer-specific antibodies or IgG antibodies, or adenoviruses overexpressing <i>Pros1</i> or <i>Luciferase</i> were injected intravenously. Mice were euthanized at day 30 or 36, respectively. The KRN serum transfer arthritis model was induced by two intraperitoneal injections of arthritic K/BxN serum in either Mer-deficient or wild-type (WT) mice, or in mice that overexpress <i>Pros1</i> or <i>Luciferase</i> in their knee joints. Mice were euthanized at day 7 or day 14, respectively. From all mice, serum was taken for cytokine profiling and knee joints were isolated for either synovial gene expression or histology and immunohistochemistry. <h3>Results</h3> Adenoviral overexpression of the Mer ligand <i>Pros1</i> resulted in reduced production of pro-inflammatory cytokines and chemokines by macrophages, compared to <i>Luciferase</i>. In addition, local <i>Pros1</i> overexpression resulted in reduced expression of pro-inflammatory and pro-destructive mediators by synovial cells of arthritic mice. Systemic and local <i>Pros1</i> overexpression diminished joint pathology, reduced the number of cleaved Caspase 3-positive apoptotic cells and secondary necrotic neutrophils. Conversely, inhibiting Mer-mediated efferocytosis by either Mer-specific antibodies or <i>Mertk</i> gene ablation resulted in aggravation of arthritis compared to controls, as evidenced by increased inflammation and tissue destruction. Additionally, Mer-inhibited mice had increased numbers of apoptotic cells in their knee joints, and higher serum levels of IL-16C, a cytokine released by secondary necrotic neutrophils. <h3>Conclusions</h3> Together, these results demonstrate that Mer locally plays a unique protective role in knee joint disease by enhancing resolution of arthritis. Our data suggest that promoting and/or restoring Mer-mediated uptake of apoptotic cells in the arthritic joint might be therapeutically beneficial. <h3>Disclosure of Interest</h3> None declared