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CXCR2 antagonism promotes oligodendrocyte precursor cell differentiation and enhances remyelination in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by the autoimmune attack of oligodendrocytes, leading to demyelination and progressive functional deficits. CXC chemokine receptor 2 (CXCR2) is recently reported to orchestrate the migration, proliferation and differ...

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Published in:Neurobiology of disease 2020-02, Vol.134, p.104630-104630, Article 104630
Main Authors: Wang, Lu, Yang, Hanyu, Zang, Caixia, Dong, Yi, Shang, Junmei, Chen, Jiajing, Wang, Yue, Liu, Hui, Zhang, Zihong, Xu, Heng, Bao, Xiuqi, Zhang, Dan
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Language:English
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Summary:Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by the autoimmune attack of oligodendrocytes, leading to demyelination and progressive functional deficits. CXC chemokine receptor 2 (CXCR2) is recently reported to orchestrate the migration, proliferation and differentiation of oligodendrocyte precursor cells (OPCs), which implies its possible involvement in the demyelinating process. Here, we used a CXCR2 antagonist, compound 2, as a tool to investigate the role of CXCR2 in demyelination and the underlying mechanism. The primary cultured oligodendrocytes and cuprizone (CPZ)-intoxicated mice were applied in the present study. The results showed that compound 2 significantly promoted OPC proliferation and differentiation. In the demyelinated lesions of CPZ-intoxicated mice, vigorous OPC proliferation and myelin repair was observed after compound 2 treatment. Subsequent investigation of the underlying mechanisms identified that upon inhibition of CXCR2, compound 2 treatment upregulated Ki67, transcription factor 2 (Olig2) and Caspr expression, activated PI3K/AKT/mTOR signaling, ultimately promoted OPCs differentiation and enhanced remyelination. In conclusion, our results demonstrated that CXCR2 antagonism efficiently promoted OPC differentiation and enhanced remyelination in CPZ-intoxicated mice, supporting CXCR2 as a promising therapeutic target for the treatment of chronic demyelinating diseases such as MS. [Display omitted] •Compound 2 promotes OPCs proliferation and differentiation.•Compound 2 enhances remyelination in a MS mouse model.•Inhibition of CXCR2 activates PI3K/AKT/mTOR signaling pathway.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2019.104630