Skip to main content

Advertisement

SpringerLink
Log in

Neuregulin1-β Decreases IL-1β-Induced Neutrophil Adhesion to Human Brain Microvascular Endothelial Cells

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Neuroinflammation contributes to the pathophysiology of diverse diseases including stroke, traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, resulting in neurodegeneration and loss of neurological function. The response of the microvascular endothelium often contributes to neuroinflammation. One such response is the upregulation of endothelial adhesion molecules which facilitate neutrophil adhesion to the endothelium and their migration from blood to tissue. Neuregulin-1 (NRG1) is an endogenous growth factor which has been reported to have anti-inflammatory effects in experimental stroke models. We hypothesized that NRG1 would decrease the endothelial response to inflammation and result in a decrease in neutrophil adhesion to endothelial cells. We tested this hypothesis in an in vitro model of cytokine-induced endothelial injury, in which human brain microvascular endothelial cells (BMECs) were treated with IL-1β, along with co-incubation with vehicle or NRG1-β. Outcome measures included protein levels of endothelial ICAM-1, VCAM-1, and E-selectin, as well as the number of neutrophils that adhere to the endothelial monolayer. Our data show that NRG1-β decreased the levels of VCAM-1, E-selectin, and neutrophil adhesion to brain microvascular endothelial cells activated by IL1-β. These findings open new possibilities for investigating NRG1 in neuroprotective strategies in brain injury.

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

Abbreviations

ICAM-1:

Intercellular cell adhesion molecule

IL-1β:

Interleukin-1 beta

NRG1-β:

Neuregulin 1-beta

VCAM-1:

Vascular cell adhesion molecule-1 or vascular cell adhesion protein-1

References

  1. Brothers HM, Bardou I, Hopp SC, Marchalant Y, Kaercher RM, Turner SM, et al. Time-dependent compensatory responses to chronic neuroinflammation in hippocampus and brainstem: the potential role of glutamate neurotransmission. J Alzheimers Dis Parkinsonism. 2013;3:110. doi:10.4172/2161-0460.1000110.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Winter CD, Iannotti F, Pringle AK, Trikkas C, Clough GF, Church MK. A microdialysis method for the recovery of IL-1beta, IL-6 and nerve growth factor from human brain in vivo. J Neurosci Methods. 2002;119(1):45–50.

    Article  CAS  PubMed  Google Scholar 

  3. Woodroofe MN, Sarna GS, Wadhwa M, Hayes GM, Loughlin AJ, Tinker A, et al. Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol. 1991;33(3):227–36.

    Article  CAS  PubMed  Google Scholar 

  4. Boato F, Rosenberger K, Nelissen S, Geboes L, Peters EM, Nitsch R, et al. Absence of IL-1beta positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury. J Neuroinflammation. 2013;10:6. doi:10.1186/1742-2094-10-6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, et al. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci. 2013;33(11):5053–64. doi:10.1523/JNEUROSCI.4361-12.2013.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res. 2013. doi:10.1016/j.neures.2013.10.004.

    PubMed  Google Scholar 

  7. Brooks TA, Hawkins BT, Huber JD, Egleton RD, Davis TP. Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations. Am J Physiol Heart Circ Physiol. 2005;289(2):H738–43. doi:10.1152/ajpheart.01288.2004.

    Article  CAS  PubMed  Google Scholar 

  8. Bevilacqua MP, Gimbrone Jr MA. Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost. 1987;13(4):425–33. doi:10.1055/s-2007-1003519.

    Article  CAS  PubMed  Google Scholar 

  9. Finnie JW. Neuroinflammation: beneficial and detrimental effects after traumatic brain injury. Inflammopharmacology. 2013;21(4):309–20. doi:10.1007/s10787-012-0164-2.

    Article  CAS  PubMed  Google Scholar 

  10. Lok J, Zhao S, Leung W, Seo JH, Navaratna D, Wang X, et al. Neuregulin-1 effects on endothelial and blood-brain-barrier permeability after experimental injury. Transl Stroke Res. 2012;3 Suppl 1:S119–24. doi:10.1007/s12975-012-0157-x.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Mellergard P, Aneman O, Sjogren F, Saberg C, Hillman J. Differences in cerebral extracellular response of interleukin-1beta, interleukin-6, and interleukin-10 after subarachnoid hemorrhage or severe head trauma in humans. Neurosurgery. 2011;68(1):12–9. doi:10.1227/NEU.0b013e3181ef2a40. discussion 9.

    Article  PubMed  Google Scholar 

  12. Hutchinson PJ, O’Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KL, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma. 2007;24(10):1545–57. doi:10.1089/neu.2007.0295.

    Article  PubMed  Google Scholar 

  13. Rigor RR, Beard Jr RS, Litovka OP, Yuan SY. Interleukin-1beta-induced barrier dysfunction is signaled through PKC-theta in human brain microvascular endothelium. Am J Physiol Cell Physiol. 2012;302(10):C1513–22. doi:10.1152/ajpcell.00371.2011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Ridder DA, Lang MF, Salinin S, Roderer JP, Struss M, Maser-Gluth C, et al. TAK1 in brain endothelial cells mediates fever and lethargy. J Exp Med. 2011;208(13):2615–23. doi:10.1084/jem.20110398.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Mako V, Czucz J, Weiszhar Z, Herczenik E, Matko J, Prohaszka Z, et al. Proinflammatory activation pattern of human umbilical vein endothelial cells induced by IL-1beta, TNF-alpha, and LPS. Cytom A. 2010;77(10):962–70. doi:10.1002/cyto.a.20952.

    Article  Google Scholar 

  16. Schaff U, Mattila PE, Simon SI, Walcheck B. Neutrophil adhesion to E-selectin under shear promotes the redistribution and co-clustering of ADAM17 and its proteolytic substrate L-selectin. J Leukoc Biol. 2008;83(1):99–105. doi:10.1189/jlb.0507304.

    Article  CAS  PubMed  Google Scholar 

  17. Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003;284(1):14–30.

    Article  CAS  PubMed  Google Scholar 

  18. Rieff HI, Raetzman LT, Sapp DW, Yeh HH, Siegel RE, Corfas G. Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells. J Neurosci. 1999;19(24):10757–66.

    CAS  PubMed  Google Scholar 

  19. Rio C, Rieff HI, Qi P, Khurana TS, Corfas G. Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron. 1997;19(1):39–50.

    Article  CAS  PubMed  Google Scholar 

  20. Kwon OB, Longart M, Vullhorst D, Hoffman DA, Buonanno A. Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J Neurosci. 2005;25(41):9378–83. doi:10.1523/JNEUROSCI.2100-05.2005.

    Article  CAS  PubMed  Google Scholar 

  21. Fisahn A, Neddens J, Yan L, Buonanno A. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex. 2009;19(3):612–8. doi:10.1093/cercor/bhn107.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Ozaki M, Sasner M, Yano R, Lu HS, Buonanno A. Neuregulin-beta induces expression of an NMDA-receptor subunit. Nature. 1997;390(6661):691–4. doi:10.1038/37795.

    CAS  PubMed  Google Scholar 

  23. Tan GH, Liu YY, Hu XL, Yin DM, Mei L, Xiong ZQ. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci. 2012;15(2):258–66. doi:10.1038/nn.3005.

    Article  CAS  Google Scholar 

  24. Ting AK, Chen Y, Wen L, Yin DM, Shen C, Tao Y, et al. Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci. 2011;31(1):15–25. doi:10.1523/JNEUROSCI.2538-10.2011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, et al. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci. 2008;28(10):2624–32. doi:10.1523/JNEUROSCI.5245-07.2008.

    Article  CAS  PubMed  Google Scholar 

  26. Norton N, Moskvina V, Morris DW, Bray NJ, Zammit S, Williams NM, et al. Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(1):96–101. doi:10.1002/ajmg.b.30236.

    Article  CAS  PubMed  Google Scholar 

  27. Makinodan M, Rosen KM, Ito S, Corfas G. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science. 2012;337(6100):1357–60. doi:10.1126/science.1220845.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Iivanainen E, Paatero I, Heikkinen SM, Junttila TT, Cao R, Klint P, et al. Intra- and extracellular signaling by endothelial neuregulin-1. Exp Cell Res. 2007;313(13):2896–909. doi:10.1016/j.yexcr.2007.03.042.

    Article  CAS  PubMed  Google Scholar 

  29. Kalinowski A, Plowes NJ, Huang Q, Berdejo-Izquierdo C, Russell RR, Russell KS. Metalloproteinase-dependent cleavage of neuregulin and autocrine stimulation of vascular endothelial cells. FASEB J Off Publ Fed Am Soc Exp Biol. 2010;24(7):2567–75. doi:10.1096/fj.08-129072.

    CAS  Google Scholar 

  30. Russell KS, Stern DF, Polverini PJ, Bender JR. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol. 1999;277(6 Pt 2):H2205–11.

    CAS  PubMed  Google Scholar 

  31. Lok J, Wang H, Murata Y, Zhu HH, Qin T, Whalen MJ, et al. Effect of neuregulin-1 on histopathological and functional outcome after controlled cortical impact in mice. J Neurotrauma. 2007;24(12):1817–22. doi:10.1089/neu.2007.0372.

    Article  PubMed  Google Scholar 

  32. Dimayuga FO, Ding Q, Keller JN, Marchionni MA, Seroogy KB, Bruce-Keller AJ. The neuregulin GGF2 attenuates free radical release from activated microglial cells. J Neuroimmunol. 2003;136(1–2):67–74.

    Article  CAS  PubMed  Google Scholar 

  33. Mencel M, Nash M, Jacobson C. Neuregulin upregulates microglial alpha7 nicotinic acetylcholine receptor expression in immortalized cell lines: implications for regulating neuroinflammation. PLoS One. 2013;8(7):e70338. doi:10.1371/journal.pone.0070338.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Asp L, Beraki S, Kristensson K, Ogren SO, Karlsson H. Neonatal infection with neurotropic influenza A virus affects working memory and expression of type III Nrg1 in adult mice. Brain Behav Immun. 2009;23(6):733–41. doi:10.1016/j.bbi.2009.04.004.

    Article  CAS  PubMed  Google Scholar 

  35. Xu Z, Jiang J, Ford G, Ford BD. Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun. 2004;322(2):440–6. doi:10.1016/j.bbrc.2004.07.149.

    Article  CAS  PubMed  Google Scholar 

  36. Kanakry CG, Li Z, Nakai Y, Sei Y, Weinberger DR. Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer. PLoS One. 2007;2(12):e1369. doi:10.1371/journal.pone.0001369.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Marballi K, Quinones MP, Jimenez F, Escamilla MA, Raventos H, Soto-Bernardini MC, et al. In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation. J Mol Med (Berl). 2010;88(11):1133–41. doi:10.1007/s00109-010-0653-y.

    Article  CAS  Google Scholar 

  38. Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA, et al. Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci. 2010;30(15):5437–50. doi:10.1523/JNEUROSCI.5169-09.2010.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Finigan JH, Mishra R, Vasu VT, Silveira LJ, Nethery DE, Standiford TJ, et al. Bronchoalveolar lavage neuregulin-1 is elevated in acute lung injury and correlates with inflammation. Eur Respir J. 2013;41(2):396–401. doi:10.1183/09031936.00004912.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Maki T, Hayakawa K, Pham LD, Xing C, Lo EH, Arai K. Biphasic mechanisms of neurovascular unit injury and protection in CNS diseases. CNS Neurol Disord Drug Targets. 2013;12(3):302–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Grimmig B, Diamond DM, et al. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One. 2013;8(1):e53376. doi:10.1371/journal.pone.0053376.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB. The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol. 2011;95(2):213–28. doi:10.1016/j.pneurobio.2011.08.005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Safa RN, Peng XY, Pentassuglia L, Lim CC, Lamparter M, Silverstein C, et al. Neuregulin-1beta regulation of embryonic endothelial progenitor cell survival. Am J Physiol Heart Circ Physiol. 2011;300(4):H1311–9. doi:10.1152/ajpheart.01104.2009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Hedhli N, Dobrucki LW, Kalinowski A, Zhuang ZW, Wu X, Russell 3rd RR, et al. Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis. Cardiovasc Res. 2012;93(3):516–24. doi:10.1093/cvr/cvr352.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by the following grants:

R37NS037074-13 (EHL)

R01NS076694-02(EHL)

P01NS055104-05 (EHL)

K08N5057339-04 (JL)

China Scholarship Council (#201206170107; LW)

The authors thank Dr. Mark Vangel and Dr. Hang Lee (Harvard Catalyst) for statistical support.

The authors thank Dr. Kayakawa for his help in learning the neutrophil assay protocol.

Conflict of Interest

Limin Wu, Samantha Walas, Wendy Leung, David Sykes, Jiang Wu, Eng H. Lo, and Josephine Lok declare that they have no conflict of interest.

Compliance with Ethics Requirements

This article does not contain any studies with human subjects.

All institutional and national guidelines for the care and use of laboratory animals were followed.

Author information

Authors and Affiliations

  1. Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Limin Wu, Samantha Walas, Wendy Leung, Eng H. Lo & Josephine Lok

  2. Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, China

    Limin Wu & Jiang Wu

  3. Department of Pediatrics, Division of Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Josephine Lok

  4. Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David B. Sykes

  5. The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA

    David B. Sykes

Authors
  1. Limin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samantha Walas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wendy Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David B. Sykes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eng H. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Josephine Lok
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Josephine Lok.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, L., Walas, S., Leung, W. et al. Neuregulin1-β Decreases IL-1β-Induced Neutrophil Adhesion to Human Brain Microvascular Endothelial Cells. Transl. Stroke Res. 6, 116–124 (2015). https://doi.org/10.1007/s12975-014-0347-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-014-0347-9

Keywords

Search

Navigation