Mechanistic description
Astrocyte-produced PGE2 (via COX2 induction) engages microglial EP2 receptors, elevating cAMP and activating PKA. PKA phosphorylates NF-κB p65(S276), altering transcriptional kinetics. Simultaneously, PKA activates SIRT1, which deacetylates H4K16 at trained enhancers, destabilizing the epigenetic memory complex (BET proteins + BRD4). Strong pharmacological tractability due to existing EP2 agonists.
Evidence for (8)
PGE2-EP2 signaling suppresses microglial inflammation via cAMP/PKA
SIRT1 activation resets trained immunity in macrophages
EP2 receptor modulation reduces neuroinflammation in Alzheimer's models
Restoring metabolism of myeloid cells reverses cognitive decline in ageing.
Cyclooxygenase-1 deletion in 5 × FAD mice protects against microglia-induced neuroinflammation and mitigates cognitive impairment.
EP2 Receptor Signaling Regulates Microglia Death.
Suppression of inflammation with conditional deletion of the prostaglandin E2 EP2 receptor in macrophages and brain microglia.
Novel Microglia Cell Line Expressing the Human EP2 Receptor.
Evidence against (2)
PGE2 signaling has complex, often pro-inflammatory roles depending on receptor subtype (EP2 vs EP4)
Systemic COX2 inhibition associated with cardiovascular risks limits therapeutic window
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