We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Astrocytic tight junctions control inflammatory CNS lesion pathogenesis.
- Authors
Sam Horng; Therattil, Anthony; Moyon, Sarah; Gordon, Alexandra; Kim, Karla; Argaw, Azeb Tadesse; Yuko Hara; Mariani, John N.; Sawai, Setsu; Flodby, Per; Crandall, Edward D.; Borok, Zea; Sofroniew, Michael V.; Chapouly, Candice; John, Gareth R.; Horng, Sam; Hara, Yuko
- Abstract
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.
- Subjects
MULTIPLE sclerosis; CENTRAL nervous system diseases; TISSUE wounds; LEUCOCYTES; BLOOD-brain barrier; ASTROCYTES; NEUROGLIA; TIGHT junctions
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 8, p3136
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI91301