Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS
Zhilin Li, … , Alexander Flügel, Kari Alitalo
Zhilin Li, … , Alexander Flügel, Kari Alitalo
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1977-1990. https://doi.org/10.1172/JCI130308.
View: Text | PDF
Research Article Autoimmunity

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

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.

Authors

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

×

Figure 7

Prophylactic ABTAA induces Tie2 activation and ameliorates EAE.

Options: View larger image (or click on image) Download as PowerPoint
Prophylactic ABTAA induces Tie2 activation and ameliorates EAE. (A) Clin...
(A) Clinical scores and percentages of body weight loss of mice induced with active EAE and treated with hIgG1 versus ABTAA prophylactically (Ab administration started at the time of EAE induction, 0 dpi) (n = 10 per group). (B) Tie2 phosphorylation in the lungs of EAE mice treated with hIgG1 versus ABTAA prophylactically (n = 3 per group) at 14 dpi by immunoprecipitation and Western blot (WB) detections with anti-phosphotyrosine (pY) and anti-Tie2 Abs. (C) Representative images and quantification of P-selectin in the SC blood vessels of hIgG1- versus ABTAA-treated EAE mice (n = 7 per group) at 14 dpi. Scale bars: 100 μm. Mean ± SEM, nonparametric Mann-Whitney U test (A, comparison of AUC values of clinical EAE scores over the disease course), 2-way repeated measures ANOVA (A, percentage of body weight loss), 1-way ANOVA with Bonferroni’s post hoc test for multiple comparisons (B), and 2-tailed Student’s t test (C). *P < 0.05; **P < 0.01.