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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.

Horng S1,2,3, Therattil A1,2,3, Moyon S1,2,3,4, Gordon A1,2,3, Kim K1,2,3, Argaw AT1,2,3, Hara Y1,4, Mariani JN1,2,3, Sawai S1,2,3, Flodby P5, Crandall ED5, Borok Z5, Sofroniew MV6, Chapouly C1,2,3, John GR1,2,3.

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.

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How did you come to the assumption that the second barrier may be therapeutically targetable? Your findings indicate that there are other components that make up the barrier, but yet the study only displayed a Cldn4 depleted component. Does the combination of the other components that make up the barrier have no effect which resulted in your assumption?

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Thank you for contributing to the discussion. The Guthy-Jackson Charitable Foundation shares recent research in the field of NMO for others to comment on, but we do not represent or speak for the authors of any given research paper. For more information directly from the authors of this paper, please view the paper on Pubmed, which includes more information.

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