CD14-Dependent Innate Immunity-Mediated Neuronal Damage in Vivo is Suppressed by NSAIDs and Ablation of a Prostaglandin E2 Receptor, EP2

Activated innate immune response in brain has been extensively associated with several diseases, including Alzheimer's disease, HIV-associated dementia, ischemia, head trauma, stroke, cerebral palsy, axonal degeneration in multiple sclerosis, and autism. Although initially investigated because of its role innate immune response to microorganisms, the CD14/Toll-like receptor pathway is now appreciated as a critical element in innate immune response to endogenous ligands, including fibrillar amyloid β peptides and neoantigens expressed by apoptotic cells. Here we review data on NSAID suppression of cerebral oxidative damage, as measured by F2-isoprostanes, and synaptodendritic degeneration in an in vivo model of CD14-dependent activation of glial innate immune response. Given recent concern over toxicity from protracted exposure to NSAIDs, we also review data from mice lacking specific receptors for PGE2, and show that mice lacking EP2, but not EP1, are completely protected from CD14-dependent paracrine neurotoxicity. These results suggest that EP2 may be a new and more focused target in the PG pathway to suppress innate immunity-mediated neuronal damage.