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Cited by 52Multiple Sclerosis Research StudiesBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS

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Li, Zhilin, Korhonen, Emilia A., Merlini, Arianna, Strauss, Judith, Wihuri, Eleonoora, Nurmi, Harri, Antila, Salli, Paech, Jennifer +6 more·2020·Journal of Clinical Investigation
DOI 10.1172/jci130308PMC PMC7108925
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Abstract

Angiopoietin-2 (Ang2), a ligand of the endothelial Tie2 tyrosine kinase, is involved in vascular inflammation and leakage in critically ill patients. However, the role of Ang2 in demyelinating central nervous system (CNS) autoimmune diseases is unknown. Here, we report that Ang2 is critically involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. Ang2 expression was induced in CNS autoimmunity, and transgenic mice overexpressing Ang2 specifically in endothelial cells (ECs) developed a significantly more severe EAE. In contrast, treatment with Ang2-blocking Abs ameliorated neuroinflammation and decreased spinal cord demyelination and leukocyte infiltration into the CNS. Similarly, Ang2-binding and Tie2-activating Ab attenuated the development of CNS autoimmune disease. Ang2 blockade inhibited expression of EC adhesion molecules, improved blood-brain barrier integrity, and decreased expression of genes involved in antigen presentation and proinflammatory responses of microglia and macrophages, which was accompanied by inhibition of α5β1 integrin activation in microglia. Taken together, our data suggest that Ang2 provides a target for increasing Tie2 activation in ECs and inhibiting proinflammatory polarization of CNS myeloid cells via α5β1 integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease.

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Cited by

Sorted by citations

Authors
Li, Z., Korhonen, E. A., Merlini, A., Strauss, J., Wihuri, E., Nurmi, H., Antila, S., Paech, J., Deutsch, U., Engelhardt, B., Chintharlapalli, S., Koh, G. Y., Flügel, A., & Alitalo, K.
Affiliations
  • University of Helsinki (FI)
  • Universitätsmedizin Göttingen (DE)
  • University of Bern (CH)
  • Eli Lilly (United States) (US)
  • Korea Advanced Institute of Science and Technology (KR)
Corresponding author
Alitalo, Kari
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2020-03-09
Volume
130
Issue
4
Pages
1977-1990
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci130308
PMC
PMC7108925
OpenAlex
W3011213037
Cited by
52
References
13
Citations by year
2026: 8 · 2025: 7 · 2024: 12 · 2023: 5 · 2022: 5 · 2021: 12 · 2020: 3
FWCI
4.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • BORIS (University Library Bern) (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
  • German Research Foundation (SFB 1328/1 A01)
  • Swiss National Science Foundation (PDFMP3_141773)
  • European Research Council (743155)
  • Academy of Finland (307366,314498)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
angiopoietin-2, Tie2, experimental autoimmune encephalomyelitis, multiple sclerosis, demyelination, neuroinflammation, leukocyte recruitment, blood-brain barrier, endothelial cells, alpha5beta1 integrin, microglia, macrophages, central nervous system autoimmunity
MeSH terms
Animals, Blood-Brain Barrier, Cell Movement, Encephalomyelitis, Autoimmune, Experimental, Gene Expression Regulation, Inflammation, Leukocytes, Mice, Transgenic, Multiple Sclerosis, Microglia, Integrin alpha5beta1, Angiopoietin-2, Endothelial Cells, Mice

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