Project 171887

Leukocytes and endothelial cells play key roles in inflammation and arthritis by releasing chemokines such as IL-8. IL-8 promotes the migration of neutrophils that rapidly accumulate in the inflamed and eliminate the danger. We have made the novel observation that in human monocytes, IL-8 secretion is regulated by extracellular nucleotides; blocking either the action of extracellular nucleotides or the nucleotide receptor P2Y6 prevented IL-8 expression and secretion as well as leukocyte migration to the inflammatory site. Extracellular nucleotides (ATP, ADP, UTP, UDP) are signalling molecules secreted in large amounts by injured and activated cells, especially at sites of inflammation. The signalling and functions induced by extracellular nucleotides in leukocytes and endothelial cells is a new but fast developing research area. Indeed nucleotides are suspected to regulate a variety of proinflammatory responses of these cells via a number of specific P2 receptors such as P2Y6. The concentration of extracellular nucleotides and thus the activation of P2 receptors are tightly regulated by cell surface enzymes called ectonucleotidases. We have discovered the first member of a new family of such enzymes that break down these molecules at the surface of macrophages and neutrophils. We engineered mice deficient in this enzyme, named NTPDase1 that represent a powerful tool to explore the function of nucleotides in inflammation. Our preliminary data suggests the involvement of two P2 receptors in cell migration, and we have obtained mice that do not express these receptors from a collaborator. In this project, using the mutant mice mentioned above together with various cellular and in vivo models, we will elucidate the function of nucleotide signalling in inflammation. We anticipate that our studies will lead to the identification of novel therapeutic targets that will help understand and treat inflammatory diseases such as arthritis as well as infection.