Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity
Article first published online: 26 MAY 2005
Copyright © 2005 Wiley-Liss, Inc.
Volume 52, Issue 1, pages 70–77, October 2005
How to Cite
Shie, F.-S., Montine, K. S., Breyer, R. M. and Montine, T. J. (2005), Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity. Glia, 52: 70–77. doi: 10.1002/glia.20220
- Issue published online: 15 AUG 2005
- Article first published online: 26 MAY 2005
- Manuscript Accepted: 22 MAR 2005
- Manuscript Received: 6 JAN 2005
- Nancy and Ellsworth Alvord Endowment
- Friends of Alzheimer Research
- NIH. Grant Number: R01-AG24011
- oxidative damage;
Prostaglandin (PG) E2 acts via four functionally antagonistic E-prostanoid (EP) receptors that are expressed on multiple cell types in the nervous system; these are designated EP1–4. We showed previously that EP2 null mice are protected from CD14-dependent neuronal damage in vivo following intracerebroventricular (ICV) injection of lipopolysaccharide (LPS). Clear interpretation of this neuroprotective outcome is limited because EP2 is expressed on glia and neurons. We tested the hypothesis that microglial EP2 is required for paracrine neurotoxicity following activation of innate immunity, using primary murine microglia and neuron co-cultures. We demonstrated that microglial EP2 was necessary for lipopolysaccharide (LPS)-activated microglia-mediated neurotoxicity, as well as induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). Genetic deletion of microglial iNOS, pharmacological suppression of COX-2 activity, or addition of exogenous superoxide dismutase (SOD) and catalase in the presence of EP2 also abolished neurotoxicity. This loss of paracrine neurotoxicity by EP2−/− microglia occurred in the absence of reduced cytokine levels. We conclude that microglial EP2 is critical to innate immunity-mediated paracrine damage to neurons involving COX-2 and iNOS. EP2 should be considered as a therapeutic target for suppression of microglial innate immunity-mediated damage in neurodegenerative diseases. © 2005 Wiley-Liss, Inc.