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

Yukio Takeshita, Birgit Obermeier, Anne C. Cotleur, Simona F. Spampinato, Fumitaka Shimizu, Erin Yamamoto, Yasuteru Sano, Thomas J. Kryzer, Vanda A Lennon, Takashi Kanda, Richard M. Ransohoff

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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.

Original languageEnglish (US)
Article numbere311
JournalNeurology: Neuroimmunology and NeuroInflammation
Volume4
Issue number1
DOIs
StatePublished - 2017

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ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Takeshita, Y., Obermeier, B., Cotleur, A. C., Spampinato, S. F., Shimizu, F., Yamamoto, E., Sano, Y., Kryzer, T. J., Lennon, V. A., Kanda, T., & Ransohoff, R. M. (2017). Effects of neuromyelitis optica - IgG at the blood - Brain barrier in vitro. Neurology: Neuroimmunology and NeuroInflammation, 4(1), [e311]. https://doi.org/10.1212/NXI.0000000000000311