ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia

The highly dynamic changes in microglia necessary to achieve a rapid neuroinflammatory response require a supply of energy from mitochondrial respiration, which leads to the accumulation of unfolded mitochondrial proteins. We previously reported that microglial activation is correlated with the mitochondrial unfolded protein response (UPRmt) in a kaolin-induced hydrocephalus model, but we still do not know the extent to which these changes in microglia are involved in cytokine release. Here, we investigated the activation of BV-2 cells and found that treatment with lipopolysaccharide (LPS) for 48 h increased the secretion of pro-inflammatory cytokines. This increase was accompanied by a concurrent decrease in oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), in association with the up-regulation of the UPRmt. Inhibition of the UPRmt by knockdown of ATF5, a key upstream regulator of the UPRmt, using small-interfering RNA against ATF5 (siATF5) not only increased production of the pro-inflammatory cytokines, interleukin-6 (IL-6), IL-1 beta and tumor necrosis factor-alpha (TNF-alpha), but also decreased MMP. Our results suggest that ATF5-dependent induction of the UPRmt in microglia acts as a protective mechanism during neuroinflammation and may be a potential therapeutic target for reducing neuroinflammation.