Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2.

Keene CD, Chang R, Stephen C, Nivison M, Nutt SE, Look A, Breyer RM, Horner PJ, Hevner R, Montine TJ
Am J Pathol. 2009 174 (6): 2300-9

PMID: 19389932 · PMCID: PMC2684194 · DOI:10.2353/ajpath.2009.081153

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.

MeSH Terms (17)

Animals Fluorescent Antibody Technique Hippocampus Immunity, Innate Lipopolysaccharides Mice Mice, Inbred C57BL Mice, Mutant Strains Neurogenesis Neurons Receptors, Prostaglandin E Receptors, Prostaglandin E, EP1 Subtype Receptors, Prostaglandin E, EP2 Subtype Reverse Transcriptase Polymerase Chain Reaction Stem Cells T-Box Domain Proteins Toll-Like Receptor 4

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