Mdivi-1 Modulates Macrophage/Microglial Polarization in Mice with EAE via the Inhibition of the TLR2/4-GSK3β-NF-κB Inflammatory Signaling Axis (original) (raw)

Abstract

Macrophage/microglial modulation plays a critical role in the pathogenesis of multiple sclerosis (MS), which is an inflammatory disorder of the central nervous system. Dynamin-related protein 1 is a cytoplasmic molecule that regulates mitochondrial fission. It has been proven that mitochondrial fission inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, can relieve experimental autoimmune encephalomyelitis (EAE), a preclinical animal model of MS. Whether macrophages/microglia are involved in the pathological process of Mdivi-1-treated EAE remains to be determined. Here, we studied the anti-inflammatory effect of Mdivi-1 on mice with oligodendrocyte glycoprotein peptide35-55 (MOG35-55)–induced EAE. We found that Drp1 phosphorylation at serine 616 in macrophages/microglia was decreased with Mdivi-1 treatment, which was accompanied by decreased antigen presentation capacity of the macrophages/microglia in the EAE mouse spinal cord. The Mdivi-1 treatment caused macrophage/microglia to produce low levels of proinflammatory molecules, such as CD16/32, iNOS, and TNF-α, and high levels of anti-inflammatory molecules, such as CD206, IL-10, and Arginase-1, suggesting that Mdivi-1 promoted the macrophage/microglia shift from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Moreover, Mdivi-1 was able to downregulate the expression of TRL2, TRL4, GSK-3β, and phosphorylated NF-κB-p65 and prevent NF-κB-mediated IL-1β and IL-6 production. In conclusion, these results indicate that Mdivi-1 significantly alleviates inflammation in mice with EAE by promoting M2 polarization by inhibiting TLR2/4- and GSK3β-mediated NF-κB activation.

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Funding

This work was supported by the Shanxi Scholarship Council of China (HGKY2019089), the International Key Research & Development Cooperation Plan of Datong (2019123), Doctoral research start-up funds of Shanxi Datong University (2019-B-20), the China Postdoctoral Science Foundation (2020M680912), and the Young Scientists Cultivation Project of Shanxi University of Chinese Medicine (2021PY-QN-09).

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  1. Xiaoqin Liu and Xiaojuan Zhang contributed equally to this work.

Authors and Affiliations

  1. Institute of Brain Science, Shanxi Datong University, Datong, 037009, China
    Xiaoqin Liu, Xiaojie Niu, Peijun Zhang, Guobin Song, Jiezhong Yu, Guoping Xi, Yanhua Li & Cungen Ma
  2. Department of Neurology, Yuncheng Central Hospital, Yuncheng, 044000, China
    Xiaojuan Zhang
  3. The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method To Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong, 030619, China
    Qing Wang, Lijuan Song, Yanhua Li & Cungen Ma
  4. Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Beijing Normal University, Beijing, 100875, China
    Xiuhua Xue

Authors

  1. Xiaoqin Liu
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  2. Xiaojuan Zhang
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  3. Xiaojie Niu
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  4. Peijun Zhang
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  5. Qing Wang
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  10. Lijuan Song
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  11. Yanhua Li
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  12. Cungen Ma
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Contributions

XQL and XJZ participated in the design of the study, conducted the majority of the experiments, analyzed the results, and wrote most of the manuscript. XJN and QW carried out the clinical score analysis of mice with EAE. PJZ, XHX, and JZY helped with the design and data analysis in flow cytometry experiments; GBS, GPX, and LJS helped with the confocal photomicrographs; YHL and CGM contributed to the supervision of the study.

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Correspondence toYanhua Li or Cungen Ma.

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12035_2021_2552_MOESM1_ESM.pdf

Supplementary file1 Mdivi-1 treatment reduces the clinical score and alleviates demyelination of EAE mice. The peptide MOG35-55 was used to induce the EAE model in mice. Mice with EAE were injected intraperitoneally daily with Mdivi-1(25 mg/kg in 0.1% DMSO) or 0.1% DMSO from 3 p.i. to 27 p.i. On Day 28 p.i., the lumbar cords were separated from the EAE mice. The lumbar cords were stained by LFB. (a) Clinical scores are shown for mice with EAE treated with Mdivi-1 and DMSO. (b) LFB staining in the spinal cords of mice with EAE was assessed for myelin status after treatment with Mdivi-1. Representative microphotographs for LFB staining are shown, and the ratio of demyelination in each group was compared. N=7–9. Mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. One representative of three experiments is shown. (PDF 1051 KB)

12035_2021_2552_MOESM2_ESM.pdf

Supplementary file2 Mdivi-1 reduces the expression of p38 in macrophages/microglia. On Day 28 p.i, the lumbar cords were separated from mice with EAE treated with Mdivi-1 or DMSO under anesthesia, and coimmunostaining of lumbar cords for p38 and IBa-1 was performed. Representative images of p38 distribution in IBa-1+ cells are shown, and IBa-1+p38+ signal was calculated. DAPI was used for nucleus staining. N=5–8. Mean ± SEM. ** p < 0.01. One representative of two experiments is shown. (PDF 1004 KB)

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Liu, X., Zhang, X., Niu, X. et al. Mdivi-1 Modulates Macrophage/Microglial Polarization in Mice with EAE via the Inhibition of the TLR2/4-GSK3β-NF-κB Inflammatory Signaling Axis.Mol Neurobiol 59, 1–16 (2022). https://doi.org/10.1007/s12035-021-02552-1

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