期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 4, 页码 1977-1990出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI130308
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资金
- European Research Council [743155]
- Jane and Aatos Erkko Foundation
- Jenny and Antti Wihuri Foundation
- Academy of Finland [307366, 314498]
- Finnish Brain Foundation
- Sigrid Juselius Foundation
- Magnus Ehrnrooth Foundation
- K. Albin Johanssons stiftelse
- Maud Kuistila Memorial Foundation
- Orion Research Foundation
- Oskar Oflund Foundation
- Biomedicum Helsinki Foundation
- Ida Montin Foundation
- Juhani Aho Foundation for Medical Research
- German Research Foundation [SFB 1328/1]
- Swiss National Science Foundation [PDFMP3_141773]
- Academy of Finland (AKA) [307366, 314498, 314498, 307366] Funding Source: Academy of Finland (AKA)
- European Research Council (ERC) [743155] Funding Source: European Research Council (ERC)
- Swiss National Science Foundation (SNF) [PDFMP3_141773] Funding Source: Swiss National Science Foundation (SNF)
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 alpha(5)beta(1), 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 alpha(5)beta(1), integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease.
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