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      • Record: found
      • Abstract: found
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      Is Open Access

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

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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.

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          Most cited references26

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          • Abstract: found
          • Article: not found

          Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment.

          Maria Romano, Marina Sironi, Carlo Toniatti … (1997)
          IL-6-/- mice showed impaired leukocyte accumulation in subcutaneous air pouches. Defective leukocyte accumulation was not due to a reduced migratory capacity of IL-6-/- leukocytes and was associated with a reduced in situ production of chemokines. These observations led to a reexamination of the interaction of IL-6 with endothelial cells (EC). EC express only the gp130 signal transducing chain and not the subunit-specific IL-6R and are therefore unresponsive to IL-6. However, EC are responsive to a combination of IL-6 and soluble IL-6R as measured by the activation of STAT3, chemokine expression, and augmentation of ICAM-1. Activation by IL-6-IL-6R complexes was inhibited by an IL-6 receptor antagonist and potentiated by a superagonist. Hence, in vivo and in vitro evidence supports the concept that the IL-6 system plays an unexpected positive role in local inflammatory reactions by amplifying leukocyte recruitment.
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            Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6.

            Luc Vallières, Iain Campbell, Fred Gage … (2002)
            Postnatal neurogenesis can be modulated after brain injury, but the role of the attendant expression of inflammatory mediators in such responses remains to be determined. Here we report that transgenically directed production of interleukin-6 (IL-6) by astroglia decreased overall neurogenesis by 63% in the hippocampal dentate gyrus of young adult transgenic mice. The proliferation, survival, and differentiation of neural progenitor cells labeled with the thymidine analog bromodeoxyuridine were all reduced in the granule cell layer of these mice, whereas their distribution and gliogenesis appeared normal. These effects were not a consequence of general toxicity of the IL-6 transgene, because they were manifested in the absence of neuronal death and of major changes in glial cell number and morphology. These findings suggest that long-term exposure of the brain to proinflammatory mediators such as IL-6, as is seen in certain degenerative disorders and infections, can interfere with adult neurogenesis.
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              Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models.

              Yukio Takeshita, Richard M. Ransohoff (2012)
              The blood-brain barrier (BBB) is the brain-specific capillary barrier that is critical for preventing toxic substances from entering the central nervous system (CNS). In contrast to vessels of peripheral organs, the BBB limits the exchange of inflammatory cells and mediators under physiological and pathological conditions. Clarifying these limitations and the role of chemokines in regulating the BBB would provide new insights into neuroprotective strategies in neuroinflammatory diseases. Because there is a paucity of in vitro BBB models, however, some mechanistic aspects of transmigration across the BBB still remain largely unknown. In this review, we summarize current knowledge of BBB cellular components, the multistep process of inflammatory cells crossing the BBB, functions of CNS-derived chemokines, and in vitro BBB models for transmigration, with a particular focus on new and recent findings. © 2012 John Wiley & Sons A/S.
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                Author and article information

                Contributors
                Yukio Takeshita:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Birgit Obermeier:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. I am now employee of Biogen (Postdoctoral Scientist, for 2 years), but was affiliated with the Cleveland Clinic at the time the study was performed and I have no conflicts to declare.

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Anne C. Cotleur:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. 1. Biogen, Senior Supervisor, 2years

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. 1. Employee at Biogen Nov 2014-present (myself)

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Simona F. Spampinato:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Fumitaka Shimizu:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Biogen, postdoctoral scientist, 1 years 10 month(2014.11- 2016.8)

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Erin Yamamoto:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Yasuteru Sano:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Thomas J. Kryzer:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Vanda A. Lennon:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. Vanda Lennon receives royalties from RSR/Kronus for sale of aquaporin-4 autoantibody testing kits and for commercial aquaporin-4 autoantibody testing performed outside Mayo Clinic.

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NIH R01-NS065829,?CNS Demyelinating Autoimmunity Targeting Water Channel Complexes?. Principal Investigator: S.J. Pittock Co-Investigator: V.A. Lennon Years: 2010-2015

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License fee payments, Technology or Inventions:

                1. 1) RSR/Kronus for sale of aquaporin-4 autoantibody testing kits. 2) Non-Mayo sites performing “home brew” diagnostic testing for aquaporin-4 autoantibody.

                Royalty Payments, Technology or Inventions:

                1. Dr. Lennon has a potential financial interest in the technologies listed below: “Aquaporin-4 as an aid for cancer diagnosis”.

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Takashi Kanda:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. Clinical and Experimental Neuroimmunology Editor-in- Chief 2010- Neuropathology, Editorial Advisory Board Member 2009-

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. Contract Grant Sponsor: Japan Society for the Promotion of Science - Tokyo Contract Grant Number: 25293203, 26670443

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Richard M. Ransohoff:
                Comment :

                Scientific Advisory Boards:

                1. Chemocentryx

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. BiogenIdec, speaker's honoraria Novartis, speaker's honoraria

                Editorial Boards:

                1. Neurology; N2

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Employed at present by Biogen. Work reported in this paper was completed before I joined Biogen.

                Consultancies:

                1. Pfizer Teva

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. Chemocentryx, sponsored research agreement Biogen, sponsored research agreement National MS Society

                Research Support, Government Entities:

                1. NIH: P50 NS38667 R01 NS32151 R01 NS74804 R21 NS74820 K24 NS51400

                Research Support, Academic Entities:

                1. Travel support and/or honoraria were provided for each of the following: Special Guest & Speaker Max-Planck Institute Retreat Ringberg Germany, 2009 Invited Plenary Speaker 1st Keystone Symposium on MS, Santa Fe New Mexico, 2009 Grand Rounds in Neurology, Johns Hopkins University, Baltimore, 2009 Keynote Lecture, Opening of Neuropathology Institute, Freiburg Germany, 2009 Plenary Lecture, Kick-off meeting for Neurodegeneration Research Center, Bonn, 2009 Invited Seminar, Institute for Research in Biomedicine, Bellinzona, Switzerland, 2009 Invited Speaker, FDA/NYAS Conference: ?Cytokine Therapies?, New York, 2009 Invited External Speaker ?Annual Japanese MS Workshop? Kyushu Japan 2009 Visiting Professor, Dept of Neurology, Kyushu University, Fukuoka, Japan, 2009 Consultant, Nature ?Landscape? editorial meeting on Neuroimmunology, 2009 Invited Seminar, GSK Hammersmith Hospital, London, 2009 Invited Speaker 12th International Symposium “Signaling at the BBB”, London, England, 2009 Co-organizer/Speaker ?Chemokines and Chemokine Receptors in the CNS?, Rome, 2009 Grand Rounds in Neurology, Ottawa General Hospital, Ontario, Canada, 2009 Invited Speaker, Keystone Symposium ?Alzheimer?s Disease?, Colorado, 2010 NIH EUREKA Review IRGs, 2008-2010 Invited Speaker, ASN annual meeting, Santa Fe, 2010 Invited Speaker, Nikolas Histiocytosis-X Symposium, Athens, Greece, 2010 Invited speaker, FOCIS 2010 Symposium ?Interventional Immunology?, Boston, 2010 Keynote Speaker, Neuroimmunology Symposium, Kyoto, Japan, 2010 Workshop Chair, International Congress of Immunology, Kobe, Japan 2010 Plenary Lecture, PACTRIMS, Bali, Indonesia, 2010 Symposium Organizer and Chair ANA annual meeting, San Francisco, CA, 2010 Workshop Chair, Special Interest Groups, ANA, San Francisco, CA, 2010 Invited Speaker, Theodor Kocher Institute, Bern, Switzerland, 2010 Invited Speaker/Session Chair, Cell Press Symposium “Inflammation in Disease”, Lisbon, 2010 Invited Speaker, Brazilian Society of Pharmacology 42nd Annual Meeting, Brazil, 2010 External Reviewer, DFG ?Centers of Excellence? Applications, Frankfurt, Germany, 2011 Invited Speaker, AAAS/Abelson Symposium ?Defeating AD?, Washington DC, 2011

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. SAB, Chemocentryx Employee, Biogen

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Journal
                Journal ID (nlm-ta): Neurol Neuroimmunol Neuroinflamm
                Journal ID (iso-abbrev): Neurol Neuroimmunol Neuroinflamm
                Journal ID (hwp): nnn
                Journal ID (publisher-id): NEURIMMINFL
                Title: Neurology® Neuroimmunology & Neuroinflammation
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Electronic): 2332-7812
                Publication date (Electronic): 19 December 2016
                Publication date Collection: January 2017
                Publication date PMC-release: 19 December 2016
                Volume: 4
                Issue: 1
                Electronic Location Identifier: e311
                Affiliations
                From the 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.
                Author notes
                Correspondence to Dr. Ransohoff: richard.ransohoff@ 123456biogen.com

                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.

                Article
                Publisher ID: NEURIMMINFL2015007898
                DOI: 10.1212/NXI.0000000000000311
                PMC ID: 5173350
                SO-VID: fb7d79a2-f90d-46a6-b6c2-1ea1c6ef1b9e
                Copyright © Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
                License:

                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.

                History
                Date received : 06 August 2016
                Date accepted : 02 November 2016
                Funding
                Funded by: NIH
                Award ID: K24NS51400, R21NS78420, and P50NS38667
                Categories
                Subject: 42
                Subject: 132
                Subject: Article
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