@article{cd5a387d315c456b916a3c105c315376,
title = "Astrocytic tight junctions control inflammatory CNS lesion pathogenesis",
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.",
author = "Sam Horng and Anthony Therattil and Sarah Moyon and Alexandra Gordon and Karla Kim and Argaw, {Azeb Tadesse} and Yuko Hara and Mariani, {John N.} and Setsu Sawai and Per Flodby and Crandall, {Edward D.} and Zea Borok and Sofroniew, {Michael V.} and Candice Chapouly and John, {Gareth R.}",
note = "Funding Information: This work was supported by National Institute of Neurological Disorders and Stroke (NINDS) research grants R01NS062703-06 and R01NS085103-01 (to GRJ), NINDS R01NS084030-03 (to MVS), National Heart, Lung, and Blood Institute (NHLBI) R01HL112638-04, R01HL126877-01A1, and P01HL119165-02 (to ZB) and U01HL108634-05 (to EDC), and NIH R24CA095823 (to the ISMMS Microscopy Facility). SH is the recipient of research residency training grant funding from NINDS R25NS079102-05, and a Leon Levy Fellowship in Neuroscience. Additional support was provided by National MS Society research grants RG5024 and RG-1501-02870 (to GRJ). This work was also supported by the ISMMS Graduate School (to JNM), and by the Beker Foundation, the Muzio Foundation, the Noto Foundation, and the Guthy-Jackson Charitable Foundation (to GRJ). EDC is Hastings Professor and Norris Chair of Medicine and receives support from the Whittier Foundation. ZB is Ralph Edgington Chair in Medicine and receives support from the Hastings Foundation.",
year = "2017",
month = aug,
day = "1",
doi = "10.1172/JCI91301",
language = "English",
volume = "127",
pages = "3136--3151",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}