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Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination

Molecular Psychiatry volume 20, pages 880–888 (2015)Cite this article

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Abstract

Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1−/− mice displayed enhanced disruption of the blood–brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8+ T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1−/− mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing–remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders.

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Acknowledgements

This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology of Korea (2011-0014447 and 2008-0062286 to EYC), from the Novartis Foundation for Therapeutical Research (to TC and EYC), from the US NIH Extramural Program (DE021685 and DE017138 to GH), the NIH Intramural Research Program, National Cancer Institute (to TC), the Deutsche Forschungsgemeinschaft (CH279/5-1 to TC), by a European Commission International Reintegration Grant (2010-268108, ANTIINFLDEL to TC) and the European Research Council (ENDHOMRET to TC). EC was supported by the Else Kröner-Fresenius-Stiftung, the Excellence Cluster Cardiopulmonary System (DFG; Exc147-1), the German Centre for Cardiovascular Research (BMBF) and the LOEWE Center for Gene and Cell Therapy (Hessen, Germany). We thank S Grossklaus and M Schuster for technical assistance, T Quertermous and R Kundu (Department of Medicine, Stanford University, Stanford, CA, USA) for providing Del-1−/− mice, Amgen for the IL-17RA−/− mice, the imaging core facility of the MTZ-Technische Universität Dresden for help with imaging and Yongqing Zhang, Elin Lehrmann and Kevin G Becker (National Institute of Aging, NIH, Baltimore, MD, USA) for assistance with gene expression analysis.

Author Contributions

EYC designed and performed experiments, analyzed data and wrote the manuscript; JHL designed and performed experiments, analyzed data and wrote the manuscript; AN, ME, SHL, SB, HL, MS, HK and GSC performed experiments; AC, KJC, TZ, KB, EC, JYK, SRB and SGM analyzed data; LB and KH provided important reagents; GH analyzed data and coedited the manuscript; and TC conceived the project, designed some experiments and wrote the manuscript.

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Author notes

  1. E Y Choi and J-H Lim: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea

    E Y Choi, S-H Lee, H Kim & G-S Cho

  2. Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

    E Y Choi, H Langer & T Chavakis

  3. Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany,

    E Y Choi, J-H Lim, A Neuwirth, A Chatzigeorgiou, K-J Chung & T Chavakis

  4. Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

    E Y Choi, A Chatzigeorgiou, M Samus, S R Bornstein & T Chavakis

  5. Clinic for Ophthalmology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

    M Economopoulou

  6. Department for Neurology, University Münster,

    S Bittner & S G Meuth

  7. Münster, Germany

    S Bittner & S G Meuth

  8. Medizinische Klinik III, Eberhard Karls-University Tübingen, Tübingen, Germany

    H Langer

  9. Department of Neurology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

    T Ziemssen

  10. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    K Bdeir

  11. Department of Internal Medicine, Cardiology, Goethe University Frankfurt, Frankfurt, Germany

    E Chavakis

  12. Department of Neurology, University of Ulsan College of Medicine, Seoul, Republic of Korea

    J-Y Koh

  13. Bioceros, Utrecht, The Netherlands

    L Boon

  14. Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    K Hosur & G Hajishengallis

  15. Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

    T Chavakis

  16. Center for Regenerative Therapies Dresden, Dresden, Germany

    T Chavakis

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  1. E Y Choi
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Correspondence to E Y Choi.

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Choi, E., Lim, JH., Neuwirth, A. et al. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry 20, 880–888 (2015). https://doi.org/10.1038/mp.2014.146

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