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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • E. Y. Choi - , University of Ulsan, National Institutes of Health (NIH), TUD Dresden University of Technology (Joint first author)
  • J. H. Lim - , TUD Dresden University of Technology (Joint first author)
  • A. Neuwirth - , TUD Dresden University of Technology (Author)
  • M. Economopoulou - , Department of Ophthalmology (Author)
  • A. Chatzigeorgiou - , TUD Dresden University of Technology (Author)
  • K. J. Chung - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • S. Bittner - , University of Münster (Author)
  • S. H. Lee - , University of Ulsan (Author)
  • H. Langer - , National Institutes of Health (NIH), University of Tübingen (Author)
  • M. Samus - , TUD Dresden University of Technology (Author)
  • H. Kim - , University of Ulsan (Author)
  • G. S. Cho - , University of Ulsan (Author)
  • T. Ziemssen - , Department of Neurology (Author)
  • K. Bdeir - , University of Pennsylvania (Author)
  • E. Chavakis - , University Hospital Frankfurt (Author)
  • J. Y. Koh - , University of Ulsan (Author)
  • L. Boon - , Bioceros (Author)
  • K. Hosur - , University of Pennsylvania (Author)
  • S. R. Bornstein - , Department of internal Medicine 3 (Author)
  • S. G. Meuth - , University of Münster (Author)
  • G. Hajishengallis - , University of Pennsylvania (Author)
  • T. Chavakis - , Institute of Clinical Chemistry and Laboratory Medicine, Center for Regenerative Therapies Dresden, Department of internal Medicine 3, National Institutes of Health (NIH) (Author)

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.

Details

Original languageEnglish
Pages (from-to)880-888
Number of pages9
JournalMolecular Psychiatry
Volume20
Issue number7
Publication statusPublished - 24 Jul 2015
Peer-reviewedYes

External IDs

researchoutputwizard legacy.publication#66730
researchoutputwizard legacy.publication#61284
Scopus 84932199529
PubMed 25385367
researchoutputwizard legacy.publication#65957
researchoutputwizard legacy.publication#66206