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Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS.
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.
Afiliação
  • Li Z; Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Korhonen EA; Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Merlini A; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre Göttingen, Göttingen, Germany.
  • Strauss J; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre Göttingen, Göttingen, Germany.
  • Wihuri E; Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Nurmi H; Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Antila S; Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Paech J; Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Deutsch U; Theodor Kocher Institute, University of Bern, Bern, Switzerland.
  • Engelhardt B; Theodor Kocher Institute, University of Bern, Bern, Switzerland.
  • Chintharlapalli S; Oncology Research, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.
  • Koh GY; Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.
  • Flügel A; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
  • Alitalo K; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre Göttingen, Göttingen, Germany.
J Clin Invest ; 130(4): 1977-1990, 2020 04 01.
Article em En | MEDLINE | ID: mdl-32149735
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 α5ß1 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 α5ß1 integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Movimento Celular / Células Endoteliais / Angiopoietina-2 / Encefalomielite Autoimune Experimental / Leucócitos / Esclerose Múltipla Limite: Animals Idioma: En Revista: J Clin Invest Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Finlândia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Movimento Celular / Células Endoteliais / Angiopoietina-2 / Encefalomielite Autoimune Experimental / Leucócitos / Esclerose Múltipla Limite: Animals Idioma: En Revista: J Clin Invest Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Finlândia