Microglial ectonucleotidases: Identification and functional roles

Microglial cells represent resident macrophages of the central nervous system where they resume a resting state of unknown physiological function. They are rapidly transformed into an activated state by acute pathological events affecting the nervous system. Activated microglia function in tissue repair and regeneration but may also enhance tissue damage. Cultured microglial cells express both P2Y and P2X receptors. Activation of the microglial P2X(7) receptor can result in the release of cytokines or also mediate cytotoxicity in microglial cells. Microglial cells have developed mechanisms for controlling the surrounding concentrations of free extracellular ATP via a surface-expressed ectonucleotidase chain. We analyzed the expression of the ectonucleotidases associated with resting microglia and microglia activated by two models of cerebral ischemia. Out of a plethora of enzymes with the potential to hydrolyze extracellular nucleotides, the major ectonucleotidases associated with microglia are NTPDase1, which hydrolyzes ATP and ADP, and ecto-5'-nucleotidase, which catalyzes the hydrolysis of AMP to adenosine. This is shown by enzyme histochemical analysis, immunocytochemistry, Northern hybridization, and the analysis of NTPDase1 deficient mice. Our results suggest that a major function of resting microglia could be in the lowering of interstitial levels of ATP acting either via autocrine pathways or in the ATP-involving signaling pathways between adjacent neurons and astrocytes. Enhanced activity of NTPDase1 may protect microglia, activated by various pathological settings, from overstimulation by ATP released from the injured tissue. The parallel increase in activity of ecto-5'-nucleotidase would facilitate the formation of the final hydrolysis product adenosine that exerts neuromodulatory and immunomodulatory actions and contributes to the protection of neurons. (C) 2001 Wiley-Liss, Inc.