Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes.

Autor:	Calvier L; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. calvier.laurent@gmail.com joachim.herz@utsouthwestern.edu.; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Demuth G; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Manouchehri N; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Wong C; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Sacharidou A; Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Mineo C; Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Shaul PW; Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Monson NL; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Kounnas MZ; Reelin Therapeutics Inc. La Jolla, CA 92037, USA., Stüve O; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Neurology, VA North Texas Health Care System, Medical Service, Dallas, TX 75390, USA., Herz J; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. calvier.laurent@gmail.com joachim.herz@utsouthwestern.edu.; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2020 Aug 12; Vol. 12 (556).
DOI:	10.1126/scitranslmed.aay7675
Abstrakt:	Neuroinflammation as a result of immune cell recruitment into the central nervous system (CNS) is a key pathogenic mechanism of multiple sclerosis (MS). However, current anti-inflammatory interventions depleting immune cells or directly targeting their trafficking into the CNS can have serious side effects, highlighting a need for better immunomodulatory strategies. We detected increased Reelin concentrations in the serum of patients with MS, resulting in increased endothelial permeability to leukocytes through increased nuclear factor κB-mediated expression of vascular adhesion molecules. We thus investigated the prophylactic and therapeutic potential of Reelin immunodepletion in experimental autoimmune encephalomyelitis (EAE) and further validated the results in Reelin knockout mice. Removal of plasma Reelin by either approach protected against neuroinflammation and largely abolished the neurological consequences by reducing endothelial permeability and immune cell accumulation in the CNS. Our findings suggest Reelin depletion as a therapeutic approach with an inherent good safety margin for the treatment of MS and other diseases where leukocyte extravasation is a major driver of pathogenicity. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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