The arginine deminase PAD2 is activated by ATP-induced P2X7R signaling in mast cells and modulates the disease course in an inflammatory arthritis model (BA3P.208)

Abstract

Abstract Rheumatoid arthritis is a chronic, systemic inflammatory disease. Citrulline-containing proteins are generated through posttranslational modification of arginine residues in a reaction catalyzed by the Ca2+-dependent peptidyl arginine deiminases or PAD enzymes. Plasma and synovial biopsy specimens from RA patients contain high levels of citrullinated proteins. PAD2 is highly expressed in synovial tissue of RA patients, in close association with citrullinated protein deposits, and its expression correlates with inflammation intensity. The process by which PAD2 is activated and contributes to protein citrullination during RA is unknown. We have identified mast cells as a major source of the PAD2 enzyme. Activation of the P2X7 purinergic receptor by the inflammatory “danger” signal ATP induces PAD2 activity and robust protein citrullination in mast cells. P2X7-mediated activation of PAD2 is sensitive to p38 MAPK and protein kinase C inhibitors, and PAD2 regulates the expression of the TNFR2, Adamts-9, and Rab6b transcripts in mast cells. The PAD2 enzyme and its citrullinated substrate proteins are released from mast cells on activation with ATP. Importantly, mast cells have been shown to play a key role in the development of RA. Our results suggest that P2X7 activation of mast cells may play a role in inflammation by providing PAD2 and PAD2 substrates access to the extracellular space.