| While ATP and ADP are traditionally thought of as energy intermediaries in the intracellular space, these nucleotides primarily act as signaling molecules in the extracellular space. By engaging purine receptors on the surface of leukocytes and endothelium in the vasculature, ATP and ADP can elicit inflammatory and pro-thrombotic responses. CD39, an ecto-enzyme, rapidly metabolizes extracellular nucleotides to suppress purinergic signaling cascades. Though it is well established that CD39 regulates ADP-driven thrombosis, it remained unclear whether CD39 participates in ATP/ADP driven inflammation. This led to the hypothesis that CD39 is a critical regulator of inflammation through the catabolism of extracellular nucleotides. Studies of macrophage and neutrophil flux into post-ischemic brain tissue and of atherosclerotic plaque development revealed a novel role for CD39 in the regulation of leukocyte activation. Leukocyte surface CD39 degrades ATP that would otherwise activate the P2X7 receptor, leading to a suppression of both the adhesion molecule alphaMbeta 2-integrin and the scavenger receptors SRA-1 and CD36. In the setting of ischemic stroke, CD39's mediated-reduction of adhesion molecule expression manifests as a profound suppression of leukocyte recruitment into the ischemic brains, and a concordant decrease in ischemic tissue damage. In the setting of atherosclerosis, CD39's inhibition of scavenger receptor expression limits foam cell formation and ultimately atherogenesis. In addition to modulation of leukocyte function, CD39 was shown to regulate platelet activation in both ischemic stroke and atherogenesis. Further exploration of atherosclerotic plaques revealed that laminar shear stresses, imparted by flowing blood, potently induce the expression of CD39 on the vascular endothelium in a mechanism partially dependent on Kruppel-Like Factor 2. These laminar shears create regionalization to CD39 expression and may impart certain vascular regions with either a resistance or predisposition to thrombosis and inflammation. In total, this thesis has identified extracellular nucleotide metabolism as a novel endogenous regulator of acute and chronic inflammation with implications for a variety of cardiovascular and other disease processes. |
