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Translational Stroke Research

, Volume 9, Issue 6, pp 631–642 | Cite as

Interleukin 6-Mediated Endothelial Barrier Disturbances Can Be Attenuated by Blockade of the IL6 Receptor Expressed in Brain Microvascular Endothelial Cells

  • Kinga G. Blecharz-Lang
  • Josephin Wagner
  • Alexa Fries
  • Melina Nieminen-Kelhä
  • Jörg Rösner
  • Ulf C. Schneider
  • Peter Vajkoczy
Original Article

Abstract

Compromised blood-brain barrier (BBB) by dysregulation of cellular junctions is a hallmark of many cerebrovascular disorders due to the pro-inflammatory cytokines action. Interleukin 6 (IL6) is implicated in inflammatory processes and in secondary brain injury after subarachnoid hemorrhage (SAH) but its role in the maintenance of cerebral endothelium still requires a precise elucidation. Although IL6 has been shown to exert pro-inflammatory action on brain microvascular endothelial cells (ECs), the expression of one of the IL6 receptors, the IL6R is controversially discussed. In attempt to reach more clarity in this issue, we present here an evident baseline expression of the IL6R in BBB endothelium in vivo and in an in vitro model of the BBB, the cEND cell line. A significantly increased expression of IL6R and its ligand was observed in BBB capillaries 2 days after experimental SAH in mice. In vitro, we saw IL6 administration resulting in an intracellular and extracellular elevation of IL6 protein, which was accompanied by a reduced expression of tight and adherens junctions, claudin-5, occludin, and vascular-endothelial (VE-) cadherin. By functional assays, we could demonstrate IL6-incubated brain ECs to lose their endothelial integrity that can be attenuated by inhibiting the IL6R. Blockade of the IL6R by a neutralizing antibody has reconstituted the intercellular junction expression to the control level and caused a restoration of the transendothelial electrical resistance of the cEND cell monolayer. Our findings add depth to the current understanding of the involvement of the endothelial IL6R in the loss of EC integrity implicating potential therapy options.

Keywords

Blood-brain barrier Cytokine Endothelial cells Inflammation Interleukin 6 Subarachnoid hemorrhage 

Notes

Acknowledgements

This study was financially supported by Deutsche Forschungsgemeinschaft (SFB TRR43) and Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin) to PV.

The authors are grateful to Irina Kremenetskaia for excellent technical assistance.

Author Contributions

KGBL, UCS, and PV designed the experiments and supervised the project. KGBL, JW, AF, MNK, and JR collected, analyzed, and interpreted the data. KGBL and PV interpreted the data and critically drafted and/or revised the manuscript. All authors were involved in interpretation of the data and critical revision of the manuscript, have approved the final version of the manuscript, and agree to be accountable for all aspects of the work.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that no conflict of interest exists.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

12975_2018_614_MOESM1_ESM.docx (145 kb)
Fig S1 (DOCX 144 kb)
12975_2018_614_MOESM2_ESM.docx (109 kb)
Fig S2 (DOCX 109 kb)
12975_2018_614_MOESM3_ESM.docx (90 kb)
Fig S3 (DOCX 89 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kinga G. Blecharz-Lang
    • 1
  • Josephin Wagner
    • 1
  • Alexa Fries
    • 1
  • Melina Nieminen-Kelhä
    • 1
  • Jörg Rösner
    • 2
  • Ulf C. Schneider
    • 1
    • 3
  • Peter Vajkoczy
    • 1
    • 3
    • 4
  1. 1.Charité—Universitätsmedizin Berlin, corporate of Freie Universität Berlin, Department of Experimental NeurosurgeryHumbold-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  2. 2.Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität BerlinHumboldt-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  3. 3.Charité—Universitätsmedizin Berlin, corporate of Freie Universität Berlin, Department of NeurosurgeryHumbold-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  4. 4.Charité—Universitätsmedizin Berlin, corporate of Freie Universität Berlin, Center for Stroke Research Berlin (CSB)Humbold-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany

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