Fig. 7.

Schematic representation of the suggested dynamic effects of PGE₂ on naïve and primed microglia. a Stimulation of naïve microglia with LPS activates TLR-4 leading to very rapid transcription of pro-inflammatory genes, including COX-2. COX-2 produces PGE₂ and increases the concentration of PGE₂ in the extracellular space. Although selective agonists of EP4 or EP2 exert anti-inflammatory effects, PGE₂ mainly induces anti-inflammatory effects through EP4 in naïve microglia. b During the course of classical microglial activation, EP4 receptor expression is down-regulated whereas EP2 expression increases and is found in peri-nuclear/nuclear zones enabling responses to high intracellular PGE₂. EP2 favors the induction of iNOS, NOX2, and G6PD. G6PD is involved in metabolic changes promoting glucose utilization through the pentose pathway that generates NADPH to fuel NO production by iNOS and free radical generation by NOX2. AA arachidonic acid, COX2 cyclooxygenase-2, G6PD glucose-6-phosphate dehydrogenase, HK hexokinase, TLR-4 Toll-like receptor-4, TF transcription factors, TNF-α tumor necrosis factor-α