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

The Journal of Clinical Investigation
Zhilin LiKari Alitalo

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...Continue Reading

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Citations

Jul 28, 2020·Cells·Xiang ZhaoHeikki Rauvala
Nov 3, 2020·Retina·Jeffrey S HeierCarlos Quezada-Ruiz
Mar 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Orsolya TörökAnnika Keller

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Datasets Mentioned

BETA
GSE129105

Methods Mentioned

BETA
transgenic
RNA-Seq
reverse-transcription PCR
scRNA-Seq
flow cytometry
ELISA
FACS
immunoprecipitation
Protein Assay

Software Mentioned

Fiji ImageJ
Zen Pro
Seurat package
Excel
Imaris
Seurat
Zen
Kaluza Analysis
AngioTool
GraphPad Prism

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