PT  - JOURNAL ARTICLE
AU  - Yukio Takeshita
AU  - Birgit Obermeier
AU  - Anne C. Cotleur
AU  - Simona F. Spampinato
AU  - Fumitaka Shimizu
AU  - Erin Yamamoto
AU  - Yasuteru Sano
AU  - Thomas J. Kryzer
AU  - Vanda A. Lennon
AU  - Takashi Kanda
AU  - Richard M. Ransohoff
TI  - Effects of neuromyelitis optica–IgG at the blood–brain barrier in vitro
AID  - 10.1212/NXI.0000000000000311
DP  - 2017 Jan 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e311
VI  - 4
IP  - 1
4099  - http://nn.neurology.org/content/4/1/e311.short
4100  - http://nn.neurology.org/content/4/1/e311.full
SO  - Neurol Neuroimmunol Neuroinflamm2017 Jan 01; 4
AB  - 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.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