Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat

Cell Signal. 2021 May 17:110048. doi: 10.1016/j.cellsig.2021.110048. Online ahead of print.ABSTRACTIntegrated stress response (ISR) contributes to various neuropathological processes and acting as a therapy target in CNS injuries. However, the fundamental role of ISR in regulating microglial polarization remains largely unknown. Currently no proper pharmacological approaches to reverse microglia-driven neuroinflammation in surgical brain injury (SBI) have been reported. Here we found that inhibition of the crucial ISR effector, activating transcription factor 4 (ATF4), using the RNA interference suppressed the lipopolysaccharide (LPS)-stimulated microglial M1 polarization in vitro. Interestingly, counteracting ISR with a small-molecule ISR inhibitor (ISRIB) resulted in a significant microglial M1 towards M2 phenotype switching after LPS treatment. The potential underlying mechanisms may related to downregulate the intracellular NADPH oxidase 4 (NOX4) expression under the neuroinflammatory microenvironment. Notably, ISRIB ameliorated the infiltration of microglia and improved the neurobehavioral outcomes in the SBI rat model. Overall, our findings suggest that targeting ISR exerts a novel anti-inflammatory effect on microglia via regulating M1/M2 phenotype and may represent a potential therapeutic target to overcome neuroinflammation following SBI.PMID:34015470 | DOI:10.1016/j.cellsig.2021.110048

Source: Cellular Signalling - May 20, 2021 Category: Cytology Authors: Teng-Chao Huang Lun Luo Shi-Hai Jiang Chuan Chen Hai-Yong He Chao-Feng Liang Wen-Sheng Li Hui Wang Lei Zhu Kun Wang Ying Guo Source Type: research