Actin-Binding Protein Cortactin Promotes Pathogenesis of Experimental Autoimmune Encephalomyelitis by Supporting Leukocyte Infiltration into the Central Nervous System

J Neurosci. 2020 Feb 12;40(7):1389-1404. doi: 10.1523/JNEUROSCI.1266-19.2019. Epub 2020 Jan 7.

Abstract

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 use cortactin gene-inactivated 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 gene-deficient female mice compared with WT mice. However, proliferation capacity and expression of IL-17A and IFNγ by cortactin-deficient and WT 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 with WT 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 STATEMENT Multiple sclerosis is an autoimmune neuroinflammatory disorder, based on the entry of inflammatory leukocytes into the CNS where these cells cause demyelination and neurodegeneration. Here, we use a mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, and show that gene inactivation of cortactin, an actin binding protein that modulates actin dynamics and branching, protects against neuroinflammation in experimental autoimmune encephalomyelitis. 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 multiple sclerosis.

Keywords: blood–brain barrier; leukocyte extravasation; multiple sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier*
  • Brain / immunology
  • Brain / pathology
  • Chemotaxis, Leukocyte / physiology*
  • Cortactin / deficiency
  • Cortactin / genetics
  • Cortactin / physiology*
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Leukocytes / immunology*
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Neutrophil Infiltration
  • Peptide Fragments / immunology
  • RNA, Messenger / biosynthesis
  • Real-Time Polymerase Chain Reaction
  • Spinal Cord / immunology
  • Spinal Cord / pathology
  • Spleen / immunology
  • Spleen / pathology
  • Transendothelial and Transepithelial Migration / physiology*

Substances

  • Cortactin
  • Cttn protein, mouse
  • Cytokines
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • RNA, Messenger
  • myelin oligodendrocyte glycoprotein (35-55)