Pro-resolving receptor protects against arthritis

N-3 docosapentaenoic acid-derived resolvin D5 (RvD5_{n-3 DPA}) is a specialized pro-resolving mediator that is important for the resolution of inflammation. Previous work has highlighted the protective role of RvD5_{n-3 DPA} in limiting inflammation and joint damage in arthritis. A new study sheds further light on this axis, and identifies GPR101 as the receptor responsible for mediating the pro-resolving functions of RvD5_{n-3 DPA}.

Credit: SCIEPRO/Science Photo Library

“We employed a screening approach to identify candidate G-protein-coupled receptors that might be activated by RvD5_{n-3 DPA},” reports Jesmond Dalli, corresponding author on the new study. The researchers found that one candidate — GPR101— bound RvD5_{n-3 DPA} with a high selectivity (K_d 6.9 nM) and high stereospecificity. Furthermore, this receptor was expressed on human peripheral leukocytes (neutrophils and monocytes) in the blood.

Addition of RvD5_{n-3 DPA} to human macrophages in vitro led to a dose-dependent increase in phagocytosis and efferocytosis whereas small interfering RNA (siRNA)-mediated knockdown of GPR101 reversed these effects. Similarly, treatment of human neutrophils with an antibody targeting GPR101 also limited the dose-dependent decrease in chemotaxis and migration mediated by RvD5_{n-3 DPA} in vitro.

In mice with K/B × N serum transfer-induced arthritis, treatment with RvD5_{n-3 DPA} led to improved clinical scores (compared with treatment with vehicle), and protected the mice against weight loss and joint oedema. Notably, in vivo siRNA-mediated knockdown of GPR101 reversed the anti-arthritic effects of RvD5_{n-3 DPA}.

knockdown of GPR101 reversed the anti-arthritic effects of RvD5_{n-3 DPA}

“The identification of GPR101 as a pro-resolving receptor provides new understanding as to how chronic inflammatory conditions might occur as well as targets for new therapeutics to treat inflammatory conditions including rheumatoid arthritis,” says Dalli.

The researchers plan to investigate the pathways that are promoted downstream of RvD5_{n-3 DPA}–GPR101 engagement, and whether these pathways are altered in disease. “Such investigations will enable us to establish whether disruptions in this axis might contribute to inflammatory disorders,” remarks Dalli.