Title: Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2.
Authors: Keene, C Dirk; Chang, Rubens; Stephen, Christina; Nivison, Mary; Nutt, Samuel E; Look, Amy; Breyer, Richard M; Horner, Phillip J; Hevner, Robert; Montine, Thomas J
Published In Am J Pathol, (2009 Jun)
Abstract: Prostaglandin E2 is one of several eicosanoid products of the cyclooxygenase isozymes and is a key regulator of innate immune responses; it also possesses paracrine effects on mature neurons. The prostaglandin E2 receptor family consists of four subtypes of which EP1 and EP2 are known to be expressed by microglia. Lipopolysaccharide (LPS)-induced innate immune activation leads to the degeneration of intermediate progenitor cells (IPCs) that are destined for neuronal maturation in the hippocampal subgranular zone (SGZ); these cells can be identified by the expression of the transcription factor T-box brain gene 2 (Tbr2). Importantly, depletion of LPS-induced IPCs from the SGZ is suppressed by cyclooxygenase inhibitors. We therefore tested the hypothesis that either EP1 or EP2 is critical to LPS-induced depletion of Tbr2+ IPCs from the SGZ. Expression of either EP1 or EP2 was necessary for Toll-like receptor 4-dependent innate immune-mediated depletion of these Tbr2+ IPCs in mice. Moreover, EP1 activation was directly toxic to murine adult hippocampal progenitor cells; EP2 was not expressed by these cells. Finally, EP1 modulated the response of murine primary microglia cultures to LPS but in a manner distinct from EP2. These results indicate that prostaglandin E2 signaling via either EP1 or EP2 is largely to completely necessary for Toll-like receptor 4-dependent depletion of IPCs from the SGZ and suggest further pharmacological strategies to protect this important neurogenic niche.
PubMed ID: 19389932
MeSH Terms: Animals; Fluorescent Antibody Technique; Hippocampus/cytology*; Hippocampus/immunology; Hippocampus/metabolism; Immunity, Innate; Lipopolysaccharides/immunology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neurogenesis/immunology*; Neurons/immunology; Neurons/metabolism; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E/metabolism*; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells/cytology; Stem Cells/immunology; Stem Cells/metabolism*; T-Box Domain Proteins/biosynthesis; Toll-Like Receptor 4/immunology; Toll-Like Receptor 4/metabolism*