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Mol Psychiatry. 2015 Jul;20(7):880-888. doi: 10.1038/mp.2014.146. Epub 2014 Nov 11.

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

Author information

1
Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.
2
Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA.
3
Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.
4
Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
5
Clinic for Ophthalmology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
6
Department for Neurology, University Münster, Germany.
7
Medizinische Klinik III, Eberhard Karls-University Tübingen, Tübingen, Germany.
8
Department of Neurology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
9
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
10
Department of Internal Medicine, Cardiology, Goethe University Frankfurt, Frankfurt, Germany.
11
Department of Neurology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
12
Bioceros, Utrecht, The Netherlands.
13
Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
14
Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
15
Center for Regenerative Therapies Dresden, Dresden, Germany.
#
Contributed equally

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.

PMID:
25385367
PMCID:
PMC4351922
DOI:
10.1038/mp.2014.146
[Indexed for MEDLINE]
Free PMC Article

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