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

Zhilin Li, Emilia A. Korhonen, Arianna Merlini, Judith Strauss, Eleonoora Wihuri, Harri Nurmi, Salli Antila, Jennifer Paech, Urban Deutsch, Britta Engelhardt, Sudhakar Chintharlapalli, Gou Young Koh, Alexander Flügel, Kari Alitalo

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalJournal of Clinical Investigation
Volume130
Issue number4
Pages (from-to)1977-1990
Number of pages14
ISSN0021-9738
DOIs
Publication statusPublished - 1 Apr 2020
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine
  • BLOOD-BRAIN-BARRIER
  • MULTIPLE-SCLEROSIS
  • ENDOTHELIAL-CELLS
  • SPINAL-CORD
  • MICROGLIA
  • TIE2
  • MACROPHAGES
  • ACTIVATION
  • NORMALIZATION
  • CONTRIBUTE

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