The role of extracellular sulfatase-2 in inflammation

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease whose molecular pathogenesis serves as a useful model for understanding other chronic inflammatory conditions. Activated macrophages are critical for RA pathogenesis, since they promote the inflammation that causes cartilage damage, bone remodelling, pain and irreversible disability. Macrophages are activated by stimuli in their environment, and responses to these stimuli are fine-tuned by their interactions with highly sulfated heparan sulfate (HS) glycosaminoglycans. HS is sulfated in complex patterns, but 6-O-sulfation of HS glucosamine subunits is known to be particularly important for regulating activity of many cytokines, chemokines and growth factors. 6-O-sulfation is hence tightly regulated, and it is the only HS sulfation motif that can be post-synthetically removed by the extracellular sulfatases SULF1 and SULF2. Although extensively studied in cancer and development, the effect of 6-O-sulfation on inflammation and macrophage function is unknown. In this thesis I showed that Sulf2 is mainly expressed by macrophages, monocytes and dendritic cells. Sulf2 is particularly highly expressed by protective resident alveolar macrophages in the lung and resident synovial macrophages in the joint, indicating that Sulf2 is likely to be important for maintaining homeostasis and suppressing inflammation. Moreover, Sulf2 is downregulated by many inflammatory stimuli, suggesting that downregulation of Sulf2 may enable macrophages to convert from a protective phenotype to an activated inflammatory phenotype. Phagocytosis was increased in Sulf2-deficient macrophages, while macrophage polarisation was inhibited. Sulf2-deficient bone marrow chimeras were generated to investigate the role of Sulf2 in immune function during antigen-induced arthritis (AIA) as an example of a chronic inflammatory disease. These Sulf2-deficient mice developed increased knee swelling, which was associated with an increase in pro-arthritic Th17 cells. In conclusion, SULF2 is important for maintaining homeostasis by suppressing macrophage activation, indicating that therapies reducing 6-O sulfation of HS might be effective for the treatment of RA and other chronic inflammatory diseases.