Brain inflammation is a critical factor involved in neurodegeneration. Recently, the prostaglandin E2 (PGE2) downstream members were suggested to modulate neuroinflammatory responses accompanying neurodegenerative diseases. In this study, we investigated the protective effects of prostaglandin E2 receptor 2 (EP2) during TLR3 and TLR4-driven inflammatory response using in vitro primary microglia and ex vivo organotypic hippocampal slice cultures (OHSCs). Depletion of microglia from OHSCs differentially affected TLR3 and TLR4 receptor expression. Poly(I:C) induced the production of prostaglandin E2 in OHSCs by increasing cyclooxygenase (COX-2) and microsomal prostaglandin E synthase (mPGES)-1. Besides, stimulation of OHSCs and microglia with Poly(I:C) upregulated EP2 receptor expression. Co-stimulation of OHSCs and microglia with the EP2 agonist butaprost reduced inflammatory mediators induced by LPS and Poly(I:C). In Poly(I:C) challenged OHSCs, butaprost almost restored microglia ramified morphology and reduced Iba1 immunoreactivity. Importantly, microglia depletion prevented the induction of inflammatory mediators following Poly(I:C) or LPS challenge in OHSCs. Activation of EP2 receptor reversed the Poly(I:C)/LPS-induced phosphorylation of the mitogen activated protein kinases (MAPKs) ERK, p38 MAPK and c-Jun N-terminal kinase (JNK) in microglia. Collectively, these data identify an anti-inflammatory function for EP2 signaling in diverse innate immune responses, through a mechanism that involves the mitogen-activated protein kinases pathway.
- EP2 receptor
- Inflammatory mediators