Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

J Clin Invest. 2017 Aug 1;127(8):3136-3151. doi: 10.1172/JCI91301. Epub 2017 Jul 24.


Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease.

MeSH terms

  • Animals
  • Astrocytes / cytology*
  • Blood-Brain Barrier / pathology
  • Cell Adhesion Molecules / metabolism
  • Central Nervous System / pathology*
  • Claudin-1 / metabolism
  • Claudin-4 / metabolism
  • Coculture Techniques
  • Cytokines / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Humans
  • Inflammation*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis / pathology
  • Nervous System Diseases / pathology*
  • Receptors, Cell Surface / metabolism
  • Tight Junctions*


  • Cell Adhesion Molecules
  • Claudin-1
  • Claudin-4
  • Cldn1 protein, mouse
  • Cldn4 protein, mouse
  • Cytokines
  • F11r protein, mouse
  • Receptors, Cell Surface