Abstract
Objective: To address the hypothesis that physiologic interactions between astrocytes and endothelial cells (EC) at the blood–brain barrier (BBB) are afflicted by pathogenic inflammatory signaling when astrocytes are exposed to aquaporin-4 (AQP4) antibodies present in the immunoglobulin G (IgG) fraction of serum from patients with neuromyelitis optica (NMO), referred to as NMO-IgG.
Methods: We established static and flow-based in vitro BBB models incorporating co-cultures of conditionally immortalized human brain microvascular endothelial cells and human astrocyte cell lines with or without AQP4 expression.
Results: In astrocyte–EC co-cultures, exposure of astrocytes to NMO-IgG decreased barrier function, induced CCL2 and CXCL8 expression by EC, and promoted leukocyte migration under flow, contingent on astrocyte expression of AQP4. NMO-IgG selectively induced interleukin (IL)-6 production by AQP4-positive astrocytes. When EC were exposed to IL-6, we observed decreased barrier function, increased CCL2 and CXCL8 expression, and enhanced leukocyte transmigration under flow. These effects were reversed after application of IL–6 neutralizing antibody.
Conclusions: Our results indicate that NMO-IgG induces IL-6 production by AQP4-positive astrocytes and that IL-6 signaling to EC decreases barrier function, increases chemokine production, and enhances leukocyte transmigration under flow.
GLOSSARY
- AM=
- astrocyte medium;
- AQP4=
- aquaporin-4;
- BBB=
- blood–brain barrier;
- BDNF=
- brain-derived neurotrophic factor;
- EC=
- endothelial cell;
- ESAM=
- endothelial cell–selective adhesion molecule;
- GDNF=
- glial cell line–derived neurotrophic factor;
- GFAP=
- glial fibrillary acidic protein;
- IFN=
- interferon;
- IgG=
- immunoglobulin G;
- IL=
- interleukin;
- NMO=
- neuromyelitis optica;
- PBMC=
- peripheral blood mononuclear cells;
- PDGF=
- platelet-derived growth factor;
- qRT-PCR=
- quantitative reverse transcription polymerase chain reaction;
- sIL-6R=
- soluble interleukin-6 receptor;
- TGF- β=
- transforming growth factor–β;
- VEGF=
- vascular endothelial growth factor
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.
Supplemental data at Neurology.org/nn
Editorial, page XXX
- Received August 6, 2016.
- Accepted in final form November 2, 2016.
- Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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