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

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Li , Z , Korhonen , E A , Merlini , A , Strauss , J , Wihuri , E , Nurmi , H , Antila , S , Paech , J , Deutsch , U , Engelhardt , B , Chintharlapalli , S , Koh , G Y , Flügel , A & Alitalo , K 2020 , ' Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS ' , Journal of Clinical Investigation , vol. 130 , no. 4 , pp. 1977-1990 . https://doi.org/10.1172/JCI130308

Title: Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS
Author: Li, Zhilin; Korhonen, Emilia A.; Merlini, Arianna; Strauss, Judith; Wihuri, Eleonoora; Nurmi, Harri; Antila, Salli; Paech, Jennifer; Deutsch, Urban; Engelhardt, Britta; Chintharlapalli, Sudhakar; Koh, Gou Young; Flügel, Alexander; Alitalo, Kari
Contributor: University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, Doctoral Programme in Biomedicine
University of Helsinki, Kari Alitalo / Principal Investigator
University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, HUSLAB
Date: 2020-04-01
Language: eng
Number of pages: 14
Belongs to series: Journal of Clinical Investigation
ISSN: 0021-9738
URI: http://hdl.handle.net/10138/315755
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.
Subject: 3111 Biomedicine
BLOOD-BRAIN-BARRIER
MULTIPLE-SCLEROSIS
ENDOTHELIAL-CELLS
SPINAL-CORD
MICROGLIA
TIE2
MACROPHAGES
ACTIVATION
NORMALIZATION
CONTRIBUTE
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