Abstract
BackgroundProstaglandin E2 (PGE2)-involved neuroinflammatory processes are prevalent in several neurological conditions and diseases. Amyloid burden is correlated with the activation of E-prostanoid (EP) 2 receptors by PGE2 in Alzheimer’s disease. We previously demonstrated that electromagnetic field (EMF) exposure can induce pro-inflammatory responses and the depression of phagocytosis in microglial cells, but the signaling pathways involved in phagocytosis of fibrillar β-amyloid (fAβ) in microglial cells exposed to EMF are poorly understood. Given the important role of PGE2 in neural physiopathological processes, we investigated the PGE2-related signaling mechanism in the immunomodulatory phagocytosis of EMF-stimulated N9 microglial cells (N9 cells).MethodsN9 cells were exposed to EMF with or without pretreatment with the selective inhibitors of cyclooxygenase-2 (COX-2), Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs) and antagonists of PG receptors EP1-4. The production of endogenous PGE2 was quantified by enzyme immunoassays. The phagocytic ability of N9 cells was evaluated based on the fluorescence intensity of the engulfed fluorescent-labeled fibrillar β-amyloid peptide (1-42) (fAβ42) measured using a flow cytometer and a fluorescence microscope. The effects of pharmacological agents on EMF-activated microglia were investigated based on the expressions of JAK2, STAT3, p38/ERK/JNK MAPKs, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1), and EP2 using real-time PCR and/or western blotting.ResultsEMF exposure significantly increased the production of PGE2 and decreased the phagocytosis of fluorescent-labeled fAβ42 by N9 cells. The selective inhibitors of COX-2, JAK2, STAT3, and MAPKs clearly depressed PGE2 release and ameliorated microglial phagocytosis after EMF exposure. Pharmacological agents suppressed the phosphorylation of JAK2-STAT3 and MAPKs, leading to the amelioration of the phagocytic ability of EMF-stimulated N9 cells. Antagonist studies of EP1-4 receptors showed that EMF depressed the phagocytosis of fAβ42 through the PGE2 system, which is linked to EP2 receptors.ConclusionsThis study indicates that EMF exposure could induce phagocytic depression via JAK2-STAT3- and MAPK-dependent PGE2-EP2 receptor signaling pathways in microglia. Therefore, pharmacological inhibition of PGE2 synthesis and EP2 receptors may be a potential therapeutic strategy to combat the neurobiological deterioration that follows EMF exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0762-9) contains supplementary material, which is available to authorized users.
Highlights
Prostaglandin E2 (PGE2)-involved neuroinflammatory processes are prevalent in several neurological conditions and diseases
This study indicates that Electromagnetic fields (EMFs) exposure could induce phagocytic depression via Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3)- and mitogen-activated protein kinases (MAPKs)-dependent PGE2-EP2 receptor signaling pathways in microglia
We validated that EMF exposure significantly increased microsomal prostaglandin E synthase-1 (mPGES-1) and cyclooxygenase 2 (COX-2) expressions and PGE2 release in N9 cells, which were accompanied by phagocytosis depression
Summary
Prostaglandin E2 (PGE2)-involved neuroinflammatory processes are prevalent in several neurological conditions and diseases. We previously demonstrated that electromagnetic field (EMF) exposure can induce pro-inflammatory responses and the depression of phagocytosis in microglial cells, but the signaling pathways involved in phagocytosis of fibrillar β-amyloid (fAβ) in microglial cells exposed to EMF are poorly understood. Given the important role of PGE2 in neural physiopathological processes, we investigated the PGE2-related signaling mechanism in the immunomodulatory phagocytosis of EMF-stimulated N9 microglial cells (N9 cells). We previously observed pro-inflammatory responses and a depression of phagocytic activity in EMF-stimulated N9 microglial cells (N9 cells) [9]. Much effort has been dedicated to identifying the upstream targets of COX-2-PGE2 cascades in microglia [19,20,21,22], the exact synthesis mechanisms of PGE2 underlying the salutary effect of EMF on microglial phagocytosis in AD remain largely unknown
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have