Neuroprotective Effect of Fractalkine on Radiation-induced Brain Injury Through Promoting the M2 Polarization of Microglia

Jiaojiao Wang,Huanhuan Li,Chunjin Xiong,Zhenyu Lin,Fan Tong,Chunhua Wei,Huijiao Pan,Xiaorong Dong

doi:10.1007/s12035-020-02138-3

Jiaojiao Wang, Huanhuan Li + Show 6 more

Open Access

https://doi.org/10.1007/s12035-020-02138-3

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Abstract

Radiation-induced brain injury (RIBI) is a serious complication in cancer patients receiving brain radiotherapy, and accumulating evidence suggests that microglial activation plays an important role in its pathogenesis. Fractalkine (FKN) is a crucial mediator responsible for the biological activity of microglia. In this study, the effect of FKN on activated microglial after irradiation and RIBI was explored and the underlying mechanisms were investigated. Our study demonstrated treatment with exogenous FKN diminished radiation-induced production of pro-inflammatory factors, such as IL1-β and TNFα, promoted transformation of microglial M1 phenotype to M2 phenotype after irradiation, and partially recovered the spatial memory of irradiated mice. Furthermore, upregulation of FKN/CX3CR1 via FKN lentivirus promoted radiation-induced microglial M2 transformation in the hippocampus and diminished the spatial memory injury of irradiated mice. Furthermore, while inhibiting the expression of CX3CR1, which exclusively expressed on microglia in the brain, the regulatory effect of FKN on microglia and cognitive ability of mice disappeared after radiation. In conclusion, the FKN could attenuate RIBI through the microglia polarization toward M2 phenotype by binding to CX3CR1 on microglia. Our study unveiled an important role of FKN/CX3CR1 in RIBI, indicating that promotion of FKN/CX3CR1 axis could be a promising strategy for the treatment of RIBI.

Highlights

The incidence of brain metastases has significantly increased in the past decades with improved systemic treatment [1]
We demonstrated that activation of NF-κB pathway after irradiation promoted release of proinflammatory factors, and inhibition of microglial activation decreased expression of inflammatory cytokines and attenuated structural abnormalities of mouse Radiation-induced brain injury (RIBI) model [15, 16]
We evaluated the effect of FKN and its interaction with inflammatory signaling on the M1/M2 phenotype changes and radiation-induced brain injury

Summary

Introduction

The incidence of brain metastases has significantly increased in the past decades with improved systemic treatment [1]. The exact pathological mechanism of RIBI remains ill-defined, studies have revealed microglia play an important role via release of inflammatory factors after radiation [3,4,5]. The assembly and disassembly of peripheral actin filaments can be used to promote localized changes in the structure of the plasma membrane, and phagocytosis is driven in this way to leading to phagocytosis Is this important for the uptake of essential nutrients, but it is used by immature dendritic cells to sample the surrounding tissue environment [14]. We evaluated the effect of FKN and its interaction with inflammatory signaling on the M1/M2 phenotype changes and radiation-induced brain injury

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