Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization

Yi-Wei Wang,Qin Zhou,Peng-Fei Ni,Qing-Qing Qian,Yan-Ning Qian,Xiang Zhang,Jia-Wen Xu

doi:10.1186/s12974-017-1002-7

Abstract

BackgroundNeuroinflammation, which ultimately leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. The neuroinflammatory process is characterized by the activation of glial cells such as microglia. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. Recently, it was confirmed that nonharmful levels of ER stress protected against experimental Parkinson’s disease. Here, we investigated mild ER stress-based regulation of lipopolysaccharide (LPS)-driven neuroinflammation in rats and in primary microglia.MethodsMale Sprague–Dawley (SD) rats received the intracerebroventricular injection of the ER stress activator tunicamycin (TM) with or without intraperitoneal injection of the ER stress stabilizer sodium 4-phenylbutyrate (4-PBA) 1 h before LPS administration. The levels of neuroinflammation and memory dysfunction were assessed 24 h after treatment. In addition, the effect of mild ER stress on microglia was determined in vitro.ResultsHere, we found that low doses of TM led to mild ER stress without cell or organism lethality. We showed that mild ER stress preconditioning reduced microglia activation and neuronal death as well as improved LPS-induced memory impairment in rats. In addition, pre-exposure to nonlethal doses of TM in microglia showed significant protection against LPS-induced proinflammatory cytokine production and M1/2b polarization. However, sodium 4-PBA, a compound that ameliorates ER stress, ablated this protective effect in vivo and in vitro.ConclusionsBased on our findings, we conclude that the mild ER stress not only limits the accumulation of misfolded proteins but also protects tissues from harmful endotoxemia insults. Therefore, ER stress preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.

Highlights

Neuroinflammation, which leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases
To determine the activation status of IRE1 signaling after Endoplasmic reticulum (ER) stress, we examined Spliced X-box-binding protein-1 (XBP1s), XBP1u, and p-inositol-requiring protein 1α (IRE1α) protein expression using western blotting
For TM treatment, we found that, low concentrations of TM resulted in the induction of the protein kinase RNA-like ER kinase (PERK)–eukaryotic translation initiation factor 2α (EIF2α)/IRE1-XBP1pathway, ATF4/CCAAT/enhancer-binding protein-homologous protein (CHOP) upregulation was lost by 24 h of treatment under conditions that the unfolded protein response (UPR) allowed for neuroprotection, but not at higher concentrations that promoted neuroinflammation and apoptosis

Summary

Introduction

Neuroinflammation, which leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. We investigated mild ER stress-based regulation of lipopolysaccharide (LPS)-driven neuroinflammation in rats and in primary microglia. Uncontrolled chronic neuroinflammation is known to play a key role in the progression of diverse neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD), by causing an over-production of proinflammatory cytokines [1, 2]. LPS-induced systemic inflammation in rats is frequently used as a model for studying neurodegeneration and cognitive impairment [6]. The UPR is mediated by three main signaling branches: the protein kinase RNA-like ER kinase (PERK)–eukaryotic translation initiation factor 2α (EIF2α) axis, the inositol-requiring protein 1α (IRE1α)– spliced X-box-binding protein-1 (XBP1s) axis, and activating transcription factor (ATF)-6α axis [10, 11]

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Results

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Conclusion