A pro-inflammatory mediator USP11 enhances the stability of p53 and inhibits KLF2 in intracerebral hemorrhage

Xiuqing Zhang,Tiejun Liu,Shijun Xu,Peng Gao,Wei Dong,Weiran Liu,Ming Gao,Lihua Song,Lusha Cui,Xiaoliu Dong

doi:10.1016/j.omtm.2021.01.015

Abstract

Microglial cell activation and neuroinflammation after intracerebral hemorrhage (ICH) lead to secondary brain damage. Ubiquitin-specific protease 11 (USP11) has been correlated with ICH-induced neuron apoptosis. This study aims to explore the molecular mechanism of USP11 regulating neuroinflammation in ICH. First, an ICH rat model was developed by intracranial administration of collagenase. Silencing USP11 was found to alleviate nerve injury in rats with ICH-like symptoms. Then, through loss- and gain-of-function assays, USP11 knockdown was revealed to alleviate ICH-induced symptoms, corresponding to reduced modified neurological severity scores (mNSS) value, brain water content, blood-brain barrier permeability, neuron apoptosis, microglial cell activation, neutrophil infiltration, and inflammatory factor secretion. It was subsequently shown in microglial cells that USP11 stabilized p53 by deubiquitination and p53 targeted the Kruppel-like factor 2 (KLF2) promoter to repress KLF2 transcription, thereby activating the nuclear factor κB (NF-κB) pathway. Further, rescue experiments were conducted in vivo to validate the function of the USP11/p53/KLF2/NF-κB axis in ICH-induced inflammation, which confirmed that USP11 silencing blocked the release of pro-inflammatory cytokines following ICH by downregulating p53, thus protecting against neurological impairment. Hence silencing USP11 may be a novel anti-inflammatory method for ICH treatment.

Highlights

Intracerebral hemorrhage (ICH), or cerebral bleed, represents a devastating subtype of stroke with significantly high morbidity and mortality.[1]
Our results demonstrated the neuroprotective effect of silencing Ubiquitin-specific protease 11 (USP11) supported by its contribution to protection against neuron apoptosis and neurological impairment
USP11 level was increased after ICH, while downregulation of USP11 was found to protect the rats from post-ICH neuron apoptosis, which is consistent with a previous report.[8]

Summary

Introduction

Intracerebral hemorrhage (ICH), or cerebral bleed, represents a devastating subtype of stroke with significantly high morbidity and mortality.[1] The treatment outcomes of ICH are dependent on the site, mass effect, and intracranial pressure induced by hematoma and are affected by cerebral edema secondary to perihematomal neurotoxicity or inflammatory damage and complications following delayed neurological impairment.[2] Based on improved understanding of ICH pathogenesis, pharmaceutical and molecule-targeted therapy have been demonstrated to prevent the hemorrhage, relieve the impact of cerebral edema, and improve the survival.[3,4] Notably, microglial activation is an important contributor to neuroinflammation responding to ICH, and therapeutic options aimed at mediating microglial cell function may mitigate ICH damage.[5] pathophysiological investigation on the molecular mechanism related to microglial activation-induced neuroinflammation in ICH is urgent and beneficial for developing potential therapeutic interventions.[6]. The function of USP11 has been reported in signaling transduction,[9] chromatin reorganization,[10] and cancer cell apoptosis[11] through deubiquitination and stabilization of key genes related to those processes, little is known about its role in the central nervous system and neuroinflammation

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