Actin-binding protein cortactin promotes pathogenesis of experimental autoimmune encephalomyelitis by supporting leukocyte infiltration into the central nervous system.
Average rating
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Star rating
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Issue Date
2020-01-06
Metadata
Show full item recordAbstract
Leukocyte 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.Citation
J Neurosci. 2020 Jan 6. pii: JNEUROSCI.1266-19.2019. doi: 10.1523/JNEUROSCI.1266-19.2019.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
Society for NeuroscienceJournal
The journal of neirosciencePubMed ID
31911458Type
ArticleISSN
1529-2401ae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.1266-19.2019
Scopus Count
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International