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

Background: Neuroinflammation, 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. Methods: Male 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. Results: Here, 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. Conclusions: Based 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.