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Neurol Neuroimmunol Neuroinflamm. 2016 Dec 19;4(1):e311. doi: 10.1212/NXI.0000000000000311. eCollection 2017 Jan.

Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro.

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Neuroinflammation Research Center (Y.T., B.O., A.C.C., S.F.S., F.S., E.Y., R.M.R.), Lerner Research Institute, Cleveland Clinic, OH; Department of Neurology and Clinical Neuroscience (Y.S., T.K.), Yamaguchi University Graduate School of Medicine, Japan; and Department of Laboratory Medicine and Pathology (T.J.K., V.A.L.), Mayo Clinic, Rochester, MN. Y.T. and F.S. are currently affiliated with the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan. B.O., A.C.C., and R.M.R. are currently affiliated with Neuroimmunology Research, Biogen, Cambridge, MA. S.F.S. is currently affiliated with the Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Italy.



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.


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.


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.


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.

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