Skip to main content

Advertisement

SpringerLink
Log in

MFG-E8 Selectively Inhibited Aβ-Induced Microglial M1 Polarization via NF-κB and PI3K-Akt Pathways

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Activated microglia are classified into two specific states: classically activated (M1) and alternatively activated (M2) subtypes. It is believed that the polarization of M1/M2 phenotype plays an important role in Alzheimer’s disease (AD). However, the mechanisms regulating this process remain unclear. Thus, we addressed this question focusing on milk fat globule epidermal growth factor 8 (MFG-E8). MFG-E8 is a unique protein which can bind to microglia and regulate its inflammatory responses. It is speculated that it might play a role in the balance of microglial polarization. In the current study, we used fibril Aβ42 in vitro to stimulate mouse primary microglial cultures and found subsequent M1 marker expression, along with retained M2 marker production. Then, we discovered that MFG-E8 pretreatment reversed the increased trend of M1 markers and the decreased expression of M2 markers, which were induced by Aβ42. Moreover, MFG-E8 effects could be effectively blocked by an MFG-E8 antibody. Further analysis on the signaling pathways showed that NF-κB upregulation and Akt downregulation in microglial cultures were observed after Aβ42 incubation. And the alteration of these pathways could also be reversed by MFG-E8. We then assessed the effects of NF-κB and PI3K-Akt on M1/M2 alteration using their specific inhibitors. Pyrrolidine dithiocarbamate, a NF-κB inhibitor, inhibited M1 marker expression; moreover, LY294002, an Akt inhibitor, enhanced M1 marker expression. Our study indicated the regulatory role of MFG-E8 on microglia M1/M2 alteration for the first time, providing a basis for understanding the potential role of microglia activation in AD.

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

References

  1. Sole-Domenech S, Cruz DL, Capetillo-Zarate E, Maxfield FR (2016) The endocytic pathway in microglia during health, aging and Alzheimer’s disease. Ageing Res Rev S1568-1637(16):30142–30148

    Google Scholar 

  2. Zhu D, Yang N, Liu YY, Zheng J, Ji C, Zuo PP (2016) M2 macrophage transplantation ameliorates cognitive dysfunction in amyloid-beta-treated rats through regulation of microglial polarization. J Alzheimers Dis 52:483–495

    Article  CAS  PubMed  Google Scholar 

  3. Durafourt BA, Moore CS, Zammit DA, Johnson TA, Zaguia F, Guiot MC et al (2012) Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia 60:717–727

    Article  PubMed  Google Scholar 

  4. Kumar A, Barrett JP, Alvarez-Croda DM, Stoica BA, Faden AI, Loane DJ (2016) NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury. Brain Behav Immun 58:291–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schwartz M (2010) “Tissue-repairing” blood-derived macrophages are essential for healing of the injured spinal cord: from skin-activated macrophages to infiltrating blood-derived cells? Brain Behav Immun 24:1054–1057

    Article  CAS  PubMed  Google Scholar 

  6. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B et al (2012) TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 188:1098–1107

    Article  CAS  PubMed  Google Scholar 

  7. Kawahara K, Suenobu M, Yoshida A, Koga K, Hyodo A, Ohtsuka H et al (2012) Intracerebral microinjection of interleukin-4/interleukin-13 reduces beta-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice. Neuroscience 207:243–260

    Article  CAS  PubMed  Google Scholar 

  8. Raymond A, Ensslin MA, Shur BD (2009) SED1/MFG-E8: a bi-motif protein that orchestrates diverse cellular interactions. J Cell Biochem 106:957–966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Neniskyte U, Brown GC (2013) Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid beta. J Neurochem 126:312–317

    Article  CAS  PubMed  Google Scholar 

  10. Liu Y, Yang X, Guo C, Nie P, Liu Y, Ma J (2013) Essential role of MFG-E8 for phagocytic properties of microglial cells. PLoS One 8:e55754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aziz M, Jacob A, Matsuda A, Wang P (2011) Review: milk fat globule-EGF factor 8 expression, function and plausible signal transduction in resolving inflammation. Apoptosis 16:1077–1086

    Article  CAS  PubMed  Google Scholar 

  12. Brissette MJ, Lepage S, Lamonde AS, Sirois I, Groleau J, Laurin LP et al (2012) MFG-E8 released by apoptotic endothelial cells triggers anti-inflammatory macrophage reprogramming. PLoS One 7:e36368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shi X, Zheng Z, Li J, Xiao Z, Qi W, Zhang A et al (2015) Curcumin inhibits Abeta-induced microglial inflammatory responses in vitro: involvement of ERK1/2 and p38 signaling pathways. Neurosci Lett 594:105–110

    Article  CAS  PubMed  Google Scholar 

  14. Ghosh M, Xu Y, Pearse DD (2016) Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines. J Neuroinflammation 13:9

    Article  PubMed  PubMed Central  Google Scholar 

  15. Walker DG, Lue LF (2015) Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 7:56

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ju L, Zeng H, Chen Y, Wu Y, Wang B, Xu Q (2015) Dual polarization of microglia isolated from mixed glial cell cultures. J Neurosci Res 93:1345–1352

    Article  CAS  PubMed  Google Scholar 

  17. McGeer PL, McGeer EG (2015) Targeting microglia for the treatment of Alzheimer’s disease. Expert Opin Ther Targets 19:497–506

    Article  CAS  PubMed  Google Scholar 

  18. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665

    Article  CAS  PubMed  Google Scholar 

  19. Fuller AD, Van Eldik LJ (2008) MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J NeuroImmune Pharmacol 3:246–256

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194

    Article  CAS  PubMed  Google Scholar 

  21. Sarsoza F, Saing T, Kayed R, Dahlin R, Dick M, Broadwater-Hollifield C et al (2009) A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, down syndrome and Tg2576 transgenic mouse brain. Acta Neuropathol 118:505–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Taetzsch T, Levesque S, McGraw C, Brookins S, Luqa R, Bonini MG et al (2015) Redox regulation of NF-kappaB p50 and M1 polarization in microglia. Glia 63:423–440

    Article  PubMed  Google Scholar 

  23. Wang G, Shi Y, Jiang X, Leak RK, Hu X, Wu Y et al (2015) HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3beta/PTEN/Akt axis. Proc Natl Acad Sci U S A 112:2853–2858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Choi BH, Lee DH, Kim J, Kang JH, Park CS (2016) Controls of nuclear factor-kappa B signaling activity by 5′-AMP-activated protein kinase activation with examples in human bladder cancer cells. Int Neurourol J 20:182–187

    Article  PubMed  PubMed Central  Google Scholar 

  25. Natoli G, De Santa F (2006) Shaping alternative NF-kappaB-dependent gene expression programs: new clues to specificity. Cell Death Differ 13:693–696

    Article  CAS  PubMed  Google Scholar 

  26. Wang Y, Duan W, Wang W, Wen D, Liu Y, Liu Y et al (2016) scAAV9-VEGF prolongs the survival of transgenic ALS mice by promoting activation of M2 microglia and the PI3K/Akt pathway. Brain Res 1648:1–10

    Article  CAS  PubMed  Google Scholar 

  27. Zhao Y, Zhang Q, Xi J, Xiao B, Li Y, Ma C (2015) Neuroprotective effect of fasudil on inflammation through PI3K/Akt and Wnt/beta-catenin dependent pathways in a mice model of Parkinson’s disease. Int J Clin Exp Pathol 8:2354–2364

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81500965), the Science and Technology Program of Guangzhou (Grant No. 201508020026), and the Guangzhou National Key Discipline and National Key Clinical Department.

Author information

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, No. 92 Zheshan West Road, Wuhu, Anhui Province, 241000, People’s Republic of China

    Xiaolei Shi & Zhiming Zhou

  2. Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People’s Republic of China

    Xiaolei Shi, Xiaoying Cai, Xiaotian Xu, Aiwu Zhang, Weiwei Qi & Yannan Fang

  3. Department of Neurology, Shaanxi Provincial People’s Hospital, The Third Affiliated Hospital of Xi’an Jiaotong University, Medical College of Xi’an, Xi’an, Shaanxi Province, 710086, People’s Republic of China

    Wei Di

  4. Department of Neurology, Zengcheng People’s Hospital, Zengcheng, Guangdong Province, 511300, People’s Republic of China

    Jie Li

Authors
  1. Xiaolei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoying Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Di
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaotian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aiwu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiwei Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhiming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yannan Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yannan Fang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Xiaolei Shi and Xiaoying Cai contributed equally to the study.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, X., Cai, X., Di, W. et al. MFG-E8 Selectively Inhibited Aβ-Induced Microglial M1 Polarization via NF-κB and PI3K-Akt Pathways. Mol Neurobiol 54, 7777–7788 (2017). https://doi.org/10.1007/s12035-016-0255-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-0255-y

Keywords

Search

Navigation