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
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
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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

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Figure 1

Ang2 is induced in EAE, and Ang2 blockade ameliorates EAE.

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Ang2 is induced in EAE, and Ang2 blockade ameliorates EAE. (A) Ang2 prot...
(A) Ang2 protein concentration in the serum and SC lysates at different time points after EAE induction (0 dpi: n = 4; 7 dpi: n = 4; 14 dpi: n = 5; 21 dpi: n = 4; 28 dpi: n = 3). (B) Clinical scores and percentage of body weight loss of control (Ctrl, n = 9) versus EC-Ang2 (n = 11) mice induced with active EAE. (C) Clinical scores and percentages of body weight loss of mice induced with active EAE and treated with mIgG1 versus Ang2 Ab prophylactically (starting at the time of EAE induction; 0 dpi) (n = 10 per group). (D) Clinical scores of mice induced with active EAE and treated with mIgG1 versus Ang2 Ab preemptively (starting during the effector phase of EAE at 7 dpi) (n = 10 per group). (E and F) Representative images and quantifications of MBP staining to show loss of myelin in the SC white matter from both prophylactic 14 dpi and preemptive 28 dpi groups (n = 10 per group). Scale bars: 100 μm. (G) Clinical scores of mice induced with adoptive transfer EAE and treated with mIgG1 versus Ang2 Ab starting at the time of adoptive transfer. Data are pooled from 2 independent experiments (n = 16 per group). Arrows indicate Ab injections. Mean ± SEM, 1-way ANOVA with Dunnett’s post hoc test for multiple comparisons (A), nonparametric Mann-Whitney U test (B-D, and G, comparison of AUC values of clinical EAE scores over the disease course), 2-way repeated measures ANOVA (B and C, body weight loss), and 2-tailed Student’s t test (E and F). *P < 0.05; **P < 0.01; ***P < 0.001.