Efferocytosis and anti-inflammatory signaling - two beneficial functions of the Mer receptor in rheumatoid arthritis

• Applicant: Dr. Silke Beermann
• Subject Area: Rheumatology ; Immunology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 248681539

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is accompanied by synovitis, destruction of cartilage and bone of the articulating joints and functional disability. Although the cause of the disease is unknown, it is generally believed that negative feedback mechanisms in auto-immune-driven joint inflammation are insufficient to halt the disease process. In the chronic inflammation during arthritis, pro-inflammatory mediators play a decisive role. Anti-TNFalpha therapy has become gold standard in RA treatment; however, it has considerable side effects and 30% of the patients are refractory. Furthermore, the pro-inflammatory mediators attract leukocytes into the inflamed joint. There, they die by apoptosis and need to be phagocytosed. Otherwise, they become necrotic and release components which further promote inflammation. Therefore, activation of a negative feedback mechanism inhibiting the production of pro-inflammatory mediators and increasing the uptake of apoptotic cells would be an interesting therapeutic strategy for RA. Negative regulation of inflammation can be achieved by activation of TAM (Tyro3, Axl, Mer) receptors, a family of receptor tyrosine kinases. The TAM receptor ligands, protein S (Pros1) and growth-arrest specific 6 (Gas6), can bind to phosphatidylserines on the surface of apoptotic cells and thereby induce their TAM receptor-mediated phagocytosis. This process, called efferocytosis, is mainly described for the receptor Mer. In collagen-induced arthritis (CIA), a mouse model of RA, overexpression of Pros1 or Gas6 leads to amelioration of arthritic symptoms and reduced inflammation. Furthermore, blocking Mer-mediated efferocytosis increased arthritis pathology in CIA. Thus, the TAM-mediated induction of negative feedback regulation of inflammation and increasing Mer-mediated efferocytosis is basically feasible to treat arthritis, but needs further investigation. Therefore, I will focus on the TAM receptor Mer which can exert both these functions, anti-inflammatory signalling and induction of efferocytosis. I will elucidate the role of Mer in taking up apoptotic cells in vivo under healthy and arthritic conditions. Furthermore, I will analyse the anti-inflammatory properties of the Mer-specific ligand Tubby. Finally, I will explore the effect of the different TAM ligands (Gas6, Pros1 and Tubby) in a therapeutic approach in experimental arthritis. The expected results are helpful to identify the value of Mer ligands as a complementary RA therapy and open the door for a myriad of Mer-based therapeutic strategies also in other inflammatory diseases.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Participating Institution: Medizinische Hochschule Hannover ; Zentrum für Pharmakologie und Toxikologie ; Institut für Pharmakologie
• Host: Professor Dr. Fons AJ van de Loo