USP18 Overexpression Protects against Focal Cerebral Ischemia Injury in Mice by Suppressing Microglial Activation.

The activation of inflammatory cytokines following stroke leads to neuron apoptosis and microglial activation, both of which are involved in ischemic brain damages. The ubiquitin-specific protease 18 (USP18) negatively regulated the expression of inflammatory cytokines and suppresses microglial activation. This study aims to determine whether USP18 expression protects against brain damage in ischemic models of stroke. We investigated USP18 expression, overexpression, and knockout under ischemic conditions in vitro and in vivo. Using BV2 microglial cells under oxygen and glucose deprivation (OGD) and 60 min transient middle cerebral artery occlusion (MCAO) in mice as models of ischemia, we assessed the infarct volume, the extent of neurogenesis, the expression of proinflammatory cytokines and Janus Kinases(JAKs)/Signal Transducer and Activator of Transcription pathway members. BV2 cells under OGD for 0, 6, 12, or 24 h exhibited decreased USP18 expression and increased expression of the proinflammatory cytokines including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and interferon (INF)-γ. Lentiviral overexpression of USP18 in MCAO mice significantly decreased the infarct volume and significantly increased the number of new neurons that coexpressed bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN). Additionally, microglial activation was inhibited, including the suppression of the pathway and the proinflammatory cytokines expression. In vitro experiments demonstrated that USP18 inhibited BV2 microglial activity and reduced the mRNA and protein levels of NF-κB, JAK1, p-JAK1, and in BV2 microglial cells. USP18 overexpression decreased ischemic brain injury through the suppression of microglial activation by negatively regulating the release of proinflammatory cytokines.

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