Astrocytic tight junctions control inflammatory CNS lesion pathogenesis
Résumé
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.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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