Show simple item record

dc.contributor.authorSamus, Maryna
dc.contributor.authorLi, Yu-Tung
dc.contributor.authorSorokin, Lydia
dc.contributor.authorRottner, Klemens
dc.contributor.authorVestweber, Dietmar
dc.date.accessioned2020-01-21T13:10:12Z
dc.date.available2020-01-21T13:10:12Z
dc.date.issued2020-01-06
dc.identifier.citationJ Neurosci. 2020 Jan 6. pii: JNEUROSCI.1266-19.2019. doi: 10.1523/JNEUROSCI.1266-19.2019.en_US
dc.identifier.issn1529-2401
dc.identifier.pmid31911458
dc.identifier.doi10.1523/JNEUROSCI.1266-19.2019
dc.identifier.urihttp://hdl.handle.net/10033/622099
dc.description.abstractLeukocyte entry into the central nervous system (CNS) is essential for immune surveillance, but is also the basis for the development of pathologic inflammatory conditions within the CNS such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). The actin-binding protein, cortactin, in endothelial cells is an important player in regulating the interaction of immune cells with the vascular endothelium. Cortactin has been shown to control the integrity of the endothelial barrier and to support neutrophil transendothelial migration in vitro and in vivo in the skin. Here we employ cortactin gene inactivated (cortactin--/--) male and female mice to study the role of this protein in EAE. Inducing EAE by immunization with a myelin oligodendrocyte glycoprotein peptide (MOG35-55) revealed an ameliorated disease course in cortactin--/-- female mice compared to WT mice. However, proliferation capacity and expression of IL-17A and IFNγ by cortactin-deficient and wildtype splenocytes did not differ, suggesting that the lack of cortactin does not affect induction of the immune response. Rather, cortactin deficiency caused decreased vascular permeability and reduced leukocyte infiltration into the brains and spinal cords of EAE mice. Accordingly, cortactin gene-deficient mice had smaller numbers of proinflammatory cuffs, less extensive demyelination and reduced expression levels of proinflammatory cytokines within the neural tissue compared to wildtype littermates. Thus, cortactin contributes to the development of neural inflammation by supporting leukocyte transmigration through the blood-brain barrier and, therefore, represents a potential candidate for targeting CNS autoimmunity.SIGNIFICANCE STATEMENTMultiple sclerosis (MS) is an autoimmune neuroinflammatory disorder, based on the entry of inflammatory leukocytes into the central nervous system (CNS) where these cells cause demyelination and neurodegeneration. Here, we use a mouse model for MS, experimental autoimmune encephalomyelitis (EAE), and show that gene inactivation of cortactin, an actin binding protein that modulates actin dynamics and branching, protects against neuroinflammation in EAE. Leukocyte infiltration into the CNS was inhibited in cortactin deficient mice and lack of cortactin in cultured primary brain endothelial cells inhibited leukocyte transmigration. Expression levels of proinflammatory cytokines in the CNS and induction of vascular permeability were reduced. We conclude that cortactin represents a novel potential target for the treatment of MS.en_US
dc.publisherSociety for Neuroscienceen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleActin-binding protein cortactin promotes pathogenesis of experimental autoimmune encephalomyelitis by supporting leukocyte infiltration into the central nervous system.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalThe journal of neiroscienceen_US
dc.source.journaltitleThe Journal of neuroscience : the official journal of the Society for Neuroscience


Files in this item

Thumbnail
Name:
Samus et al.pdf
Size:
10.44Mb
Format:
PDF
Description:
accepted manuscript

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-ShareAlike 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International