Activation of EP₂ receptor suppresses poly(I: C) and LPS-mediated inflammation in primary microglia and organotypic hippocampal slice cultures: Contributing role for MAPKs.

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.

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