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

• Published in: Neurology : neuroimmunology & neuroinflammation Vol. 4; no. 1; p. e311
• Main Authors: Takeshita, Yukio, Obermeier, Birgit, Cotleur, Anne C., Spampinato, Simona F., Shimizu, Fumitaka, Yamamoto, Erin, Sano, Yasuteru, Kryzer, Thomas J., Lennon, Vanda A., Kanda, Takashi, Ransohoff, Richard M.
• Format: Journal Article
• Language: English
• Published: United States American Academy of Neurology 01.01.2017; Lippincott Williams & Wilkins
• ISSN: 2332-7812; 2332-7812
• DOI: 10.1212/NXI.0000000000000311

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.