Differential regulation of microglial motility by ATP/ADP and adenosine

Microglia are motile immune-competent cells of the central nervous system. They assume a highly branched morphology and monitor the brain parenchyma under physiological conditions. In the presence of injury, microglia retract their branching processes, migrate to the site of injury, and help clear cellular debris by phagocytosis. This response appears to be mediated in part by ATP released at the site of injury. Here, we review the evidence for the involvement of ATP and the purinergic P2Y(12) receptor in microglial process extension and chemoattraction to injury. We subsequently discuss recent findings regarding a switch of this chemotactic response to ATP in activated, or proinflammatory, microglia. Specifically, in LPS-activated microglia, ATP induces process retraction and repulsive migration, effects opposite to those seen in unstimulated cells. These repulsive effects of ATP are mediated by the G(s)-coupled adenosine A(2A) receptor and depend on the breakdown of ATP to adenosine. Thus, ATP-induced repulsion by activated microglia involves upregulation of the adenosine A(2A) receptor and coincident downregulation of the P2Y(12) receptor. The roles of the A(2A) receptor in brain pathologies such as Parkinson's disease and ischemia are also examined. We propose that the effects of A(2A) receptor antagonists on brain injury may be in part due to the inactivation of A(2A) on activated microglia.