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

C. Dirk Keene, Rubens Chang, Christina Stephen, Mary Nivison, Samuel E. Nutt, Amy Look, Richard M. Breyer, Phillip J. Horner, Robert Hevner, Thomas J. Montine

Research output: Contribution to journalArticle

29 Scopus citations

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 E 2 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.

Original languageEnglish (US)
Pages (from-to)2300-2309
Number of pages10
JournalAmerican Journal of Pathology
Volume174
Issue number6
DOIs
StatePublished - Jun 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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