Ceria nanoparticles ameliorate white matter injury after intracerebral hemorrhage: microglia-astrocyte involvement in remyelination

Jingwei Zheng,Zeyu Sun,Shenbin Xu,Xiaoyu Wang,Haijian Wu,Jia’Nan Lu,Jun Yu,Feng Liang,Weilin Xu,Jianmin Zhang,Yuanjian Fang,Sheng Chen,Shuhao Mei,Ligen Shi

doi:10.1186/s12974-021-02101-6

Abstract

BackgroundIntracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration.MethodsICH was induced in vivo by collagenase VII injection. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocyte alteration, and the underlying molecular mechanisms.ResultsCeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation after ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately increased in ICH + CeNP + PLX3397-treated mice compared to the ICH + vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia.ConclusionThe present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.

Highlights

Intracerebral hemorrhage (ICH) is a serious neurological crisis that accounts for 20–30% of stroke cases in Asia, with high mortality and disability [1, 2]
The present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through reactive oxygen species (ROS)-induced NF-κB p65 translocation that hinders Oligodendrocyte progenitor cells (OPCs) maturation
A previous study demonstrated that several central nervous system (CNS) diseases resulted in reactive astrocytes, which could be transformed into the A1 phenotype via mediators (IL-1α, C1q, TNF) secreted by activated microglia [14]

Summary

Introduction

Intracerebral hemorrhage (ICH) is a serious neurological crisis that accounts for 20–30% of stroke cases in Asia, with high mortality and disability [1, 2]. A previous study demonstrated that 77% of ICH patients had white matter injury (WMI) [5]. Previous studies have demonstrated that ICH induced severe oligodendrocyte death and demyelination in white matter [8]. The process of OPC proliferation and differentiation is orchestrated by microglia and astrocytes. A previous study demonstrated that several CNS diseases resulted in reactive astrocytes, which could be transformed into the A1 phenotype via mediators (IL-1α, C1q, TNF) secreted by activated microglia [14]. Intracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration

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Discussion

Conclusion