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

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.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1002-7) contains supplementary material, which is available to authorized users.

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice

“…Infections in late embryogenesis have a detrimental and long‐term effect on cognitive function during adulthood and aging (Meyer et al, ), indicating a causal relationship between disturbances of late embryonic development and the risk of AD‐like neuropathology (Krstic et al, ). LPS is the main component of the outer membrane of gram‐negative bacteria, and systemic LPS injections trigger neuroinflammation (Wang et al, ). Exposure to LPS in early gestation is related to fetal death and resorption, but exposure to LPS in mid‐ to late gestation is associated with fetal death and preterm delivery.…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…In particular, the infiltrated immunosuppressive cells could trigger the M1/M2 shift of microglia through the secretion of anti-inflammatory cytokines, e.g., TGF-β and IL-10. Mild ER stress induced the M1/M2b polarization of microglia and alleviated the LPS-induced inflammation in rat brain [179]. There are observations that the number of Treg cells becomes increased in the blood of the patients with mild cognitive impairment (MCI) and AD [180].…”

Lactobacillus paracasei-derived extracellular vesicles attenuate the intestinal inflammatory response by augmenting the endoplasmic reticulum stress pathway

“…ER stress has been implicated in many diseases, including obesity, diabetes, inflammatory diseases, and neurodegenerative disorders [24][25][26][27] . ER stress is also a mechanism of action for anti-inflammatory agents 28 .…”