Figure 2.

P2 receptors modulate neuroinflammation. A simplified model based on the literature mentioned in this review summarizes the interactions between neurons and glial cells. Pro-inflammatory signals modulate P2X₇-mediated release of IL-1β and surface expression of P2X₄ receptors in the presence of ATP released by degenerating neurons and reactive astrocytes. On the surface of neurons, P2X₇ receptors mediate apoptosis with caspase 3-dependent expression of P2X₄ receptors as “flags” for microglial engulfment. Microglial migration to sites of insult is mediated by P2Y₁₂ and adenosine A₃ receptors and its neurophagic activity through P2Y₆ receptors. While A₁ adenosine receptors inhibit general inflammatory pathways, A_2a receptors activate COX-2 as well as retract microglial processes. In healthy neurons, truncated P2X₇ and P2Y₂ receptors enhance α-secretase activity, preventing the formation of amyloid deposits. Amyloid formation is also immediately cleared through microglial phagocytosis, mediated by P2Y₂ receptors; pinocytosis, through P2Y₄ receptors; and activity of MMP-9, inhibited by the tonic activity of P2Y₁₄ receptors.