Skip to main content

Advertisement

SpringerLink
Log in

Neuregulin-1 regulates the conversion of M1/M2 microglia phenotype via ErbB4-dependent inhibition of the NF-κB pathway

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

The inflammatory response caused by microglia in the central nervous system plays an important role in Alzheimer's disease. Neuregulin-1 (NRG1) is a member of the neuregulin family and has been demonstrated to have anti-inflammatory properties. The relationship between NRG1, microglia phenotype and neuroinflammation remains unclear.

Materials and methods

BV2 cells were used to examine the mechanism of NRG1 in regulating microglia polarization. Neuronal apoptosis, inflammatory factors TNF-α and iNOS, microglia polarization, ErbB4 and NF-κB p65 expression were assessed.

Results

We found that exogenous NRG1 treatment or overexpression improved microglial activity and reduced the secretion of the inflammatory factors TNF-α and iNOS in vitro. The expression of Bax in SH-SY5Y neuron cells incubated with medium collected from the NRG1 treatment group decreased. Additionally, our study showed that NRG1 treatment reduced the levels of the M1 microglia markers CD120 and iNOS and increased the levels of the M2 microglia markers CD206 and Arg-1. Furthermore, we observed that NRG1 treatment attenuated Aβ-induced NF-κB activation and promoted the expression of p-ErbB4 and that knockdown of ErbB4 abrogated the effects of NRG1 on NF-κB, Bax levels and M2 microglial polarization.

Conclusion

NRG1 inhibits the release of inflammatory factors in microglia and regulates the switching of the M1/M2 microglia phenotype, most likely via ErbB4-dependent inhibition of the NF-κB pathway.

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

Similar content being viewed by others

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

Abbreviations

AD:

Alzheimer’s disease

CON:

Control

ELISA:

Enzyme-linked immunosorbent assay

GFP:

Green fluorescent protein

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

NC:

Negative control

NF-κB:

Nuclear factor-kappa B

NRG1:

Neuregulin-1

OVER-N:

Overexpression-NRG1

TNF:

Tumor necrosis factor

References

  1. Sengoku R (2020) Aging and Alzheimer’s disease pathology. Neuropathology 40(1):22–29

    Article  PubMed  Google Scholar 

  2. Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada González F, Perrin P, Keren-Shaul H, Gury M, Lara-Astaiso D, Thaiss CA, Cohen M, Bahar Halpern K, Baruch K, Deczkowska A, Lorenzo-Vivas E, Itzkovitz S, Elinav E, Sieweke MH, Schwartz M, Amit I (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science 353(6301):aad8670

  3. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194

    Article  CAS  PubMed  Google Scholar 

  4. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173(4):649–665

    Article  CAS  PubMed  Google Scholar 

  5. Wang J, Xing H, Wan L, Jiang X, Wang C, Wu Y (2018) Treatment targets for M2 microglia polarization in ischemic stroke. Biomed Pharmacother 105:518–525

    Article  PubMed  Google Scholar 

  6. Cui W, Tao J, Wang Z, Ren M, Zhang Y, Sun Y, Peng Y, Li R (2013) Neuregulin1beta1 antagonizes apoptosis via ErbB4-dependent activation of PI3-kinase/Akt in APP/PS1 transgenic mice. Neurochem Res 38(11):2237–2246

    Article  CAS  PubMed  Google Scholar 

  7. Baik TK, Kim YJ, Kang SM, Song DY, Min SS, Woo RS (2016) Blocking the phosphatidylinositol 3-kinase pathway inhibits neuregulin-1-mediated rescue of neurotoxicity induced by Aβ1-42. J Pharm Pharmacol 68(8):1021–1029

    Article  CAS  PubMed  Google Scholar 

  8. Xu J, Hu C, Chen S, Shen H, Jiang Q, Huang P, Zhao W (2017) Neuregulin-1 protects mouse cerebellum against oxidative stress and neuroinflammation. Brain Res 1670:32–43

    Article  CAS  PubMed  Google Scholar 

  9. Zhao WJ (2013) The expression and localization of neuregulin-1 (Nrg1) in the gastrointestinal system of the rhesus monkey. Folia Histochem Cytobiol 51(1):38–44

    Article  CAS  PubMed  Google Scholar 

  10. Xu J, de Winter F, Farrokhi C, Rockenstein E, Mante M, Adame A, Cook J, Jin X, Masliah E, Lee KF (2016) Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer’s disease model. Sci Rep 6:31692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA, Bennett DL (2010) Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci 30(15):5437–5450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Solomon W, Wilson NO, Anderson L, Pitts S, Patrickson J, Liu M, Ford BD, Stiles JK (2014) Neuregulin-1 attenuates mortality associated with experimental cerebral malaria. J Neuroinflamm 11:9

    Article  Google Scholar 

  13. Alizadeh A, Santhosh KT, Kataria H, Gounni AS, Karimi-Abdolrezaee S (2018) Neuregulin-1 elicits a regulatory immune response following traumatic spinal cord injury. J Neuroinflamm 15(1):53

    Article  Google Scholar 

  14. Yoo SY, Yoo JY, Kim HB, Baik TK, Lee JH, Woo RS (2019) Neuregulin-1 protects neuronal cells against damage due to CoCl2-induced hypoxia by suppressing hypoxia-inducible factor-1α and P53 in SH-SY5Y cells. Int Neurourol J 23(Suppl 2):S111-118

    Article  PubMed  PubMed Central  Google Scholar 

  15. Alizadeh A, Dyck SM, Kataria H, Shahriary GM, Nguyen DH, Santhosh KT, Karimi-Abdolrezaee S (2017) Neuregulin-1 positively modulates glial response and improves neurological recovery following traumatic spinal cord injury. Glia 65(7):1152–1175

    Article  PubMed  Google Scholar 

  16. Kreutzberg GW (1995) Microglia, the first line of defence in brain pathologies. Arzneimittelforschung 45(3A):357–360

    CAS  PubMed  Google Scholar 

  17. Xiang Y, Liu T, Yang H, Gao F, Xiang H, Manyande A, Tian Y, Tian X (2015) NRG1-ErbB signalling promotes microglia activation contributing to incision-induced mechanical allodynia. Eur J Pain 19(5):686–694

    Article  CAS  PubMed  Google Scholar 

  18. Yao K, Zu HB (2020) Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease. Inflammopharmacology 28(1):95–110

    Article  PubMed  Google Scholar 

  19. Cui W, Sun C, Ma Y, Wang S, Wang X, Zhang Y (2020) Inhibition of TLR4 induces M2 microglial polarization and provides neuroprotection via the NLRP3 inflammasome in Alzheimer’s disease. Front Neurosci 14:444

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tai Y, Qiu Y, Bao Z (2018) Magnesium lithospermate B suppresses lipopolysaccharide-induced neuroinflammation in BV2 microglial cells and attenuates neurodegeneration in lipopolysaccharide-injected mice. J Mol Neurosci 64(1):80–92

    Article  CAS  PubMed  Google Scholar 

  21. Al Mamun A, Chauhan A, Yu H, Xu Y, Sharmeen R, Liu F (2018) Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice. Eur J Neurosci 47(2):140–149

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI, Loane DJ (2013) Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging 34(5):1397–1411

    Article  CAS  PubMed  Google Scholar 

  23. Caldeira C, Cunha C, Vaz AR, Falcão AS, Barateiro A, Seixas E, Fernandes A, Brites D (2017) Key aging-associated alterations in primary microglia response to beta-amyloid stimulation. Front Aging Neurosci 9:277

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xie L, Zhang N, Zhang Q, Li C, Sandhu AF, Iii GW, Lin S, Lv P, Liu Y, Wu Q, Yu S (2020) Inflammatory factors and amyloid β-induced microglial polarization promote inflammatory crosstalk with astrocytes. Aging (Albany NY) 12(22):22538–22549

    CAS  Google Scholar 

  25. Zhou J, Yu W, Zhang M, Tian X, Li Y, Lü Y (2019) Imbalance of microglial TLR4/TREM2 in LPS-treated APP/PS1 transgenic mice: a potential link between Alzheimer’s disease and systemic inflammation. Neurochem Res 44(5):1138–1151

    Article  CAS  PubMed  Google Scholar 

  26. Berköz M, Krośniak M, Özkan-Yılmaz F, Özlüer-Hunt A (2020) Prophylactic effect of Biochanin A in lipopolysaccharide-stimulated BV2 microglial cells. Immunopharmacol Immunotoxicol 42(4):330–339

    Article  PubMed  Google Scholar 

  27. Schnappauf O, Aksentijevich I (2020) Mendelian diseases of dysregulated canonical NF-κB signaling: from immunodeficiency to inflammation. J Leukoc Biol 108(2):573–589

    Article  CAS  PubMed  Google Scholar 

  28. Jha NK, Jha SK, Kar R, Nand P, Swati K, Goswami VK (2019) Nuclear factor-kappa β as a therapeutic target for Alzheimer’s disease. J Neurochem 150(2):113–137

    Article  CAS  PubMed  Google Scholar 

  29. Sivandzade F, Prasad S, Bhalerao A, Cucullo L (2019) NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol 21:101059

  30. D’Erchia AM, Gallo A, Manzari C, Raho S, Horner DS, Chiara M, Valletti A, Aiello I, Mastropasqua F, Ciaccia L, Locatelli F, Pisani F, Nicchia GP, Svelto M, Pesole G, Picardi E (2017) Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS. Sci Rep 7(1):10046

    Article  PubMed  PubMed Central  Google Scholar 

  31. Singh SS, Rai SN, Birla H, Zahra W, Rathore AS, Singh SP (2020) NF-κB-mediated neuroinflammation in Parkinson’s disease and potential therapeutic effect of polyphenols. Neurotox Res 37(3):491–507

    Article  CAS  PubMed  Google Scholar 

  32. Zhang F, Zhong R, Li S, Fu Z, Cheng C, Cai H, Le W (2017) Acute hypoxia induced an imbalanced M1/M2 activation of microglia through NF-κB signaling in Alzheimer’s disease mice and wild-type littermates. Front Aging Neurosci 9:282

    Article  PubMed  PubMed Central  Google Scholar 

  33. Janssen MJ, Leiva-Salcedo E, Buonanno A (2012) Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons. J Neurosci 32(40):13889–13895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gao R, Ji MH, Gao DP, Yang RH, Zhang SG, Yang JJ, Shen JC (2017) Neuroinflammation-induced downregulation of hippocampacal neuregulin 1-ErbB4 signaling in the parvalbumin interneurons might contribute to cognitive impairment in a mouse model of sepsis-associated encephalopathy. Inflammation 40(2):387–400

    Article  CAS  PubMed  Google Scholar 

  35. Zhang SR, Wu JL, Chen H, Luo R, Chen WJ, Tang LJ, Li XW, Yang JM, Gao TM (2020) ErbB4 knockdown in serotonergic neurons in the dorsal raphe induces anxiety-like behaviors. Neuropsychopharmacology 45(10):1698–1706

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liang X, Ding Y, Zhang Y, Chai YH, He J, Chiu SM, Gao F, Tse HF, Lian Q (2015) Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs following myocardial infarction. Cell Death Dis 6:e1765

  37. Liang X, Ding Y, Lin F, Zhang Y, Zhou X, Meng Q, Lu X, Jiang G, Zhu H, Chen Y, Lian Q, Fan H, Liu Z (2019) Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways. FASEB J 33(3):4559–4570

    Article  CAS  PubMed  Google Scholar 

  38. Cardin JA, Carlén M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai LH, Moore CI (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459(7247):663–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by funding support from the National Natural Science Foundation of China (U1804185, 81873459, U1804166), and the support project for the Disciplinary Group of Psychology and Neuroscience, Xinxiang Medical University (2016PN-KFKT-11).

Author information

Authors and Affiliations

  1. Department of Human Anatomy and Histoembryology, Xinxiang Medical University, Xinxiang, China

    Yuqi Ma, Peixia Fan, Rui Zhao, Yinghua Zhang, Xianwei Wang & Weigang Cui

  2. Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, China

    Yuqi Ma, Peixia Fan, Rui Zhao, Yinghua Zhang & Weigang Cui

  3. Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China

    Xianwei Wang

Authors
  1. Yuqi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peixia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yinghua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weigang Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WC conceived and designed the experiments. YM, PF, RZ, YZ performed the research and analyzed the data. YM and WC wrote the paper. XW gave the informative advice. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xianwei Wang or Weigang Cui.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All of the procedures and animal care were approved by Xinxiang Medical University Ethics Committee (Xinxiang, China, Permit Number: XYLL-2018-B009) and were conducted in accordance with the National Institutes of Health guidelines for the care of laboratory animals.

Informed consent

Written informed consent was obtained from all participants at the time of obtaining consent to participate.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, Y., Fan, P., Zhao, R. et al. Neuregulin-1 regulates the conversion of M1/M2 microglia phenotype via ErbB4-dependent inhibition of the NF-κB pathway. Mol Biol Rep 49, 3975–3986 (2022). https://doi.org/10.1007/s11033-022-07249-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-07249-9

Keywords

Search

Navigation