被撤回的出版物: Elevation of USP4 antagonizes oxygen glucose deprivation/reoxygenation-evoked microglia activation and neuroinflammation-mediated neurotoxicity via the TRAF6-NF-κB signaling (Retracted article. See vol. 11, pg. 4374, 2021)

An ischemic stroke is a devastating neurological disease with the typical occurrence of brain ischemia/reperfusion (I/R) injury, and it has high mortality and disability globally. Microglia activation after a stroke results in the release of pro-inflammatory cytokines that can further aggravate brain damage. A recent study confirmed the potential role of ubiquitin-specific peptidase 4 (USP4) in the injury process. Nevertheless, the role and mechanism of USP4 during an ischemic stroke remain elusive. In this research, we simulated an I/R injury by oxygen glucose deprivation/reoxygenation (OGD/R) in vitro and confirmed the obvious down-regulation of USP4 in microglia under OGD/R conditions. Moreover, USP4 elevation antagonized the OGD/R-induced microglia proliferation and activation by suppressing the NO levels and the expression of the microglial marker IBA-1. Additionally, the overexpression of USP4 suppressed the release of microglia activation-induced pro-inflammatory cytokines, including IL-1 beta, IL-6, and TNF-alpha. Intriguingly, incubation with the conditioned medium from the microglia under OGD/R conditions induced neurotoxicity by inhibiting cell viability and increasing the LDH release, apoptosis, and caspase-3 activity, which were reversed following USP4 overexpression. Mechanism analysis corroborated that USP4 up-regulation repressed the OGD/R-induced activation of TRAF6-NF-kappa B signaling. Notably, restoring the TRAF6 signaling ameliorated the suppressive effects of USP4 elevation on microglia activation, inflammation, and the subsequent neuron injury. These findings suggest that USP4 may alleviate ischemic stroke by restraining microglia-mediated neuro-inflammation and neurotoxicity via the TRAF6-NF-kappa B pathway, due to which it is a promising therapeutic agent against strokes.