Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2.
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.
Keene
C Dirk
CD
Department of Pathology, University of Washington, Box 359791, Seattle, WA 98104, USA.
Chang
Rubens
R
Stephen
Christina
C
Nivison
Mary
M
Nutt
Samuel E
SE
Look
Amy
A
Breyer
Richard M
RM
Horner
Phillip J
PJ
Hevner
Robert
R
Montine
Thomas J
TJ
D000818:Animals; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055495:Neurogenesis / Q000276:immunology*; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
C491198:Eomes protein, mouse; D008070:Lipopolysaccharides; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020825:T-Box Domain Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4