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Activation of EP 2 receptor suppresses poly(I: C) and LPS‐mediated inflammation in primary microglia and organotypic hippocampal slice cultures: Contributing role for MAPKs
Author(s) -
Yousif Nizar M.,
de Oliveira Antonio Carlos Pinheiro,
Brioschi Simone,
Huell Michael,
Biber Knut,
Fiebich Bernd L.
Publication year - 2018
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23276
Subject(s) - microglia , tlr4 , p38 mitogen activated protein kinases , biology , prostaglandin e2 receptor , microbiology and biotechnology , mapk/erk pathway , receptor , kinase , inflammation , signal transduction , tlr3 , agonist , innate immune system , toll like receptor , immunology , biochemistry
Abstract Brain inflammation is a critical factor involved in neurodegeneration. Recently, the prostaglandin E 2 (PGE 2 ) downstream members were suggested to modulate neuroinflammatory responses accompanying neurodegenerative diseases. In this study, we investigated the protective effects of prostaglandin E 2 receptor 2 (EP 2 ) 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 E 2 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 EP 2 receptor expression. Co‐stimulation of OHSCs and microglia with the EP 2 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 EP 2 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 EP 2 signaling in diverse innate immune responses, through a mechanism that involves the mitogen‐activated protein kinases pathway.