biostudies-literatureHorng SNHLBI NIH HHSNINDS NIH HHSNCI NIH HHS3136-3151https://www.ebi.ac.uk/biostudies/studies/S-EPMC5531407biostudies-literatureUnknown127(8)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.The Journal of clinical investigationAstrocytic tight junctions control inflammatory CNS lesion pathogenesis.PMC5531407P01 HL119165R01 HL112638R24 CA095823R01 NS085103U01 HL108634R25 NS079102R01 HL126877R01 NS084030R01 NS062703Sawai SJohn GRArgaw ATBorok ZKim KHara YTherattil AMariani JNFlodby PMoyon SCrandall EDHorng SSofroniew MVChapouly CGordon AfalseAstrocytic tight junctions control inflammatory CNS lesion pathogenesis.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.2017-01-01T00:00:00Z2017 Aug2021-02-21T03:44:00Z2019-03-27T02:51:52ZS-EPMC55314072873750910.1172/jci9130110.1172/JCI91301