Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

References

  1. Duffy SS, Lees JG, Moalem-Taylor G (2014) The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int 2014:285245. https://doi.org/10.1155/2014/285245

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chastain EM, Duncan DS, Rodgers JM (1812) Miller SD (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 2:265–274. https://doi.org/10.1016/j.bbadis.2010.07.008

    Article  CAS  Google Scholar 

  3. Correale J, Marrodan M, Ysrraelit MC (2019) Mechanisms of neurodegeneration and axonal dysfunction in progressive multiple sclerosis. Biomedicines 7(1):14. https://doi.org/10.3390/biomedicines7010014

    Article  CAS  PubMed Central  Google Scholar 

  4. Das A, Sinha M, Datta S, Abas M, Chaffee S, Sen CK, Roy S (2015) Monocyte and macrophage plasticity in tissue repair and regeneration. Am J Pathol 185(10):2596–2606. https://doi.org/10.1016/j.ajpath.2015.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chu F, Shi M, Zheng C, Shen D, Zhu J, Zheng X, Cui L (2018) The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol 318:1–7. https://doi.org/10.1016/j.jneuroim.2018.02.015

    Article  CAS  PubMed  Google Scholar 

  6. Funes SC, Rios M, Escobar-Vera J, Kalergis AM (2018) Implications of macrophage polarization in autoimmunity. Immunology 154(2):186–195. https://doi.org/10.1111/imm.12910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buck MD, O’Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ et al (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166(1):63–76. https://doi.org/10.1016/j.cell.2016.05.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505(7483):335–343. https://doi.org/10.1038/nature12985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12(8):2245–2256. https://doi.org/10.1091/mbc.12.8.2245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Baek SH, Park SJ, Jeong JI, Kim SH, Han J, Kyung JW, Baik SH, Choi Y, Choi BY, Park JS et al (2017) Inhibition of Drp1 ameliorates synaptic depression, abeta deposition, and cognitive impairment in an Alzheimer’s disease model. J Neurosci 37(20):5099–5110. https://doi.org/10.1523/JNEUROSCI.2385-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14(2):193–204. https://doi.org/10.1016/j.devcel.2007.11.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cui M, Ding H, Chen F, Zhao Y, Yang Q, Dong Q (2016) Mdivi-1 protects against ischemic brain injury via elevating extracellular adenosine in a cAMP/CREB-CD39-dependent manner. Mol Neurobiol 53(1):240–253. https://doi.org/10.1007/s12035-014-9002-4

    Article  CAS  PubMed  Google Scholar 

  13. Wu Q, Gao C, Wang H, Zhang X, Li Q, Gu Z, Shi X, Cui Y, Wang T, Chen X et al (2018) Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. Int J Biochem Cell Biol 94:44–55. https://doi.org/10.1016/j.biocel.2017.11.007

    Article  CAS  PubMed  Google Scholar 

  14. Li YH, Xu F, Thome R, Guo MF, Sun ML, Song GB, Li RL, Chai Z, Ciric B, Rostami AM et al (2019) Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis. J Neuroinflammation 16(1):149. https://doi.org/10.1186/s12974-019-1542-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thome R, Moore JN, Mari ER, Rasouli J, Hwang D, Yoshimura S, Ciric B, Zhang GX, Rostami AM (2017) Induction of peripheral tolerance in ongoing autoimmune inflammation requires interleukin 27 signaling in dendritic cells. Front Immunol 8:1392. https://doi.org/10.3389/fimmu.2017.01392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Imaizumi K, Suzuki T, Kojima M, Shimomura M, Sakuyama N, Tsukada Y, Sasaki T, Nishizawa Y, Taketomi A, Ito M et al (2020) Ki67 expression and localization of T cells after neoadjuvant therapies as reliable predictive markers in rectal cancer. Cancer Sci 111(1):23–35. https://doi.org/10.1111/cas.14223

    Article  CAS  PubMed  Google Scholar 

  17. Becher B, Tugues S, Greter M (2016) GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45(5):963–973. https://doi.org/10.1016/j.immuni.2016.10.026

    Article  CAS  PubMed  Google Scholar 

  18. Giridharan S, Srinivasan M (2018) Mechanisms of NF-kappaB p65 and strategies for therapeutic manipulation. J Inflamm Res 11:407–419. https://doi.org/10.2147/JIR.S140188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu Y, Yin H, Zhao M, Lu Q (2014) TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol 47(2):136–147. https://doi.org/10.1007/s12016-013-8402-y

    Article  CAS  PubMed  Google Scholar 

  20. Poltavets AS, Vishnyakova PA, Elchaninov AV, Sukhikh GT, Fatkhudinov TK (2020) Macrophage modification strategies for efficient cell therapy. Cells 9(6):1535. https://doi.org/10.3390/cells9061535

    Article  CAS  PubMed Central  Google Scholar 

  21. Yi L, Huang X, Guo F, Zhou Z, Chang M, Huan J (2017) GSK-3beta-dependent activation of GEF-H1/ROCK signaling promotes LPS-induced lung vascular endothelial barrier dysfunction and acute lung injury. Front Cell Infect Microbiol 7:357. https://doi.org/10.3389/fcimb.2017.00357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li Z, Zhu H, Liu C, Wang Y, Wang D, Liu H, Cao W, Hu Y, Lin Q, Tong C et al (2019) GSK-3beta inhibition protects the rat heart from the lipopolysaccharide-induced inflammation injury via suppressing FOXO3A activity. J Cell Mol Med 23(11):7796–7809. https://doi.org/10.1111/jcmm.14656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu JG, Zhao D, Gong Q, Bao F, Chen WW, Zhang H, Xu MH (2020) Development of bisindole-substituted aminopyrazoles as novel GSK-3beta inhibitors with suppressive effects against microglial inflammation and oxidative neurotoxicity. ACS Chem Neurosci 11(20):3398–3408. https://doi.org/10.1021/acschemneuro.0c00520

    Article  CAS  PubMed  Google Scholar 

  24. Sorrentino V, Menzies KJ, Auwerx J (2018) Repairing mitochondrial dysfunction in disease. Annu Rev Pharmacol Toxicol 58:353–389. https://doi.org/10.1146/annurev-pharmtox-010716-104908

    Article  CAS  PubMed  Google Scholar 

  25. Wang W, Yin J, Ma X, Zhao F, Siedlak SL, Wang Z, Torres S, Fujioka H, Xu Y, Perry G et al (2017) Inhibition of mitochondrial fragmentation protects against Alzheimer’s disease in rodent model. Hum Mol Genet 26(21):4118–4131. https://doi.org/10.1093/hmg/ddx299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Feng ST, Wang ZZ, Yuan YH, Wang XL, Sun HM, Chen NH, Zhang Y (2020) Dynamin-related protein 1: a protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson’s disease. Pharmacol Res 151:104553. https://doi.org/10.1016/j.phrs.2019.104553

    Article  CAS  PubMed  Google Scholar 

  27. Rosdah AA, Holien JK, Delbridge LM, Dusting GJ, Lim SY (2016) Mitochondrial fission - a drug target for cytoprotection or cytodestruction? Pharmacol Res Perspect 4(3):e00235. https://doi.org/10.1002/prp2.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bruck W (2005) The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J Neurol 252(Suppl 5):v3-9. https://doi.org/10.1007/s00415-005-5002-7

    Article  CAS  PubMed  Google Scholar 

  29. Halmer R, Walter S, Fassbender K (2014) Sphingolipids: important players in multiple sclerosis. Cell Physiol Biochem 34(1):111–118. https://doi.org/10.1159/000362988

    Article  CAS  PubMed  Google Scholar 

  30. Marim FM, Silveira TN, Lima DS Jr, Zamboni DS (2010) A method for generation of bone marrow-derived macrophages from cryopreserved mouse bone marrow cells. PLoS ONE 5(12):e15263. https://doi.org/10.1371/journal.pone.0015263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM, Van Den Berg TK, De Groot CJ, Van Der Valk P, Dijkstra CD (2005) CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51(4):297–305. https://doi.org/10.1002/glia.20208

    Article  PubMed  Google Scholar 

  32. Wang J, Wang J, Wang J, Yang B, Weng Q, He Q (2019) Targeting microglia and macrophages: a potential treatment strategy for multiple sclerosis. Front Pharmacol 10:286. https://doi.org/10.3389/fphar.2019.00286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lan X, Han X, Li Q, Yang QW, Wang J (2017) Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol 13(7):420–433. https://doi.org/10.1038/nrneurol.2017.69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJM et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16(9):1211–1218. https://doi.org/10.1038/nn.3469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jiang HR, Milovanovic M, Allan D, Niedbala W, Besnard AG, Fukada SY, Alves-Filho JC, Togbe D, Goodyear CS, Linington C et al (2012) IL-33 attenuates EAE by suppressing IL-17 and IFN-gamma production and inducing alternatively activated macrophages. Eur J Immunol 42(7):1804–1814. https://doi.org/10.1002/eji.201141947

    Article  CAS  PubMed  Google Scholar 

  36. Weng Q, Wang J, Wang J, Wang J, Sattar F, Zhang Z, Zheng J, Xu Z, Zhao M, Liu X et al (2018) Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization. Cell Death Dis 9(2):251. https://doi.org/10.1038/s41419-018-0290-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen C, Li YH, Zhang Q, Yu JZ, Zhao YF, Ma CG, Xiao BG (2014) Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis. Acta Pharmacol Sin 35(11):1428–1438. https://doi.org/10.1038/aps.2014.68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang J, Zheng Y, Luo Y, Du Y, Zhang X, Fu J (2019) Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/ TLR4/ NF-kappaB pathways in BV2 cells. Mol Immunol 116:29–37. https://doi.org/10.1016/j.molimm.2019.09.020

    Article  CAS  PubMed  Google Scholar 

  39. Jaworski T (2020) Control of neuronal excitability by GSK-3beta: epilepsy and beyond. Biochim Biophys Acta Mol Cell Res 1867(9):118745. https://doi.org/10.1016/j.bbamcr.2020.118745

    Article  CAS  PubMed  Google Scholar 

  40. Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W, Bailey R, Maric D, Zenklusen JC, Lee J et al (2008) Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation. Cancer Res 68(16):6643–6651. https://doi.org/10.1158/0008-5472

    Article  PubMed  PubMed Central  Google Scholar 

  41. Li L, Chen J, Lin L, Pan G, Zhang S, Chen H, Zhang M, Xuan Y, Wang Y, You Z (2020) Quzhou Fructus Aurantii Extract suppresses inflammation via regulation of MAPK, NF-kappaB, and AMPK signaling pathway. Sci Rep 10(1):1593. https://doi.org/10.1038/s41598-020-58566-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vermeulen L, De Wilde G, Van Damme P, VandenBerghe W, Haegeman G (2003) Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22(6):1313–1324. https://doi.org/10.1093/emboj/cdg139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Guo X, Harada C, Namekata K, Matsuzawa A, Camps M, Ji H, Swinnen D, Jorand-Lebrun C, Muzerelle M, Vitte PA et al (2010) Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol Med 2(12):504–515. https://doi.org/10.1002/emmm.201000103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. De Santa F, Vitiello L, Torcinaro A, Ferraro E (2019) The role of metabolic remodeling in macrophage polarization and its effect on skeletal muscle regeneration. Antioxid Redox Signal 30(12):1553–1598. https://doi.org/10.1089/ars.2017.7420

    Article  CAS  PubMed  Google Scholar 

  45. O’Neill LA, Pearce EJ (2016) Immunometabolism governs dendritic cell and macrophage function. J Exp Med 213(1):15–23. https://doi.org/10.1084/jem.20151570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yu B, Ma J, Li J, Wang D, Wang Z, Wang S (2020) Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics. Nat Commun 11(1):2549. https://doi.org/10.1038/s41467-020-16312-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yao CH, Wang R, Wang Y, Kung CP, Weber JD, Patti GJ (2019) Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation. Elife 8. https://doi.org/10.7554/eLife.41351

  48. Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A, Yadava N, Ge SX et al (2017) The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev Cell 40(6):583-594 e586. https://doi.org/10.1016/j.devcel.2017.02.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li W, Feng J, Gao C, Wu M, Du Q, Tsoi B, Wang Q, Yang D, Shen J (2019) Nitration of Drp1 provokes mitophagy activation mediating neuronal injury in experimental autoimmune encephalomyelitis. Free Radic Biol Med 143:70–83. https://doi.org/10.1016/j.freeradbiomed.2019.07.037

    Article  CAS  PubMed  Google Scholar 

  50. Almolda B, Gonzalez B, Castellano B (2011) Antigen presentation in EAE: role of microglia, macrophages and dendritic cells. Front Biosci (Landmark Ed) 16:1157–1171. https://doi.org/10.2741/3781

    Article  CAS  Google Scholar 

Download references

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).

Author information

Author notes

  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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaojuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaojie Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peijun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiuhua Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guobin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiezhong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guoping Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lijuan Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yanhua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Cungen Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Yanhua Li or Cungen Ma.

Ethics declarations

Ethics Approval

Animal experimental protocols have been approved by the Institutional Animal Care and Use Committees of Shanxi Datong University. No human study was performed.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

The participant has consented to the submission of the case report to the journal.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02552-1

Keywords

Search

Navigation