Astrocytic tight junctions control inflammatory CNS lesion pathogenesis
Sam Horng, … , Candice Chapouly, Gareth R. John
Sam Horng, … , Candice Chapouly, Gareth R. John
Published July 24, 2017
Citation Information: J Clin Invest. 2017;127(8):3136-3151. https://doi.org/10.1172/JCI91301.
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Research Article Immunology Neuroscience

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.

Authors

Sam Horng, Anthony Therattil, Sarah Moyon, Alexandra Gordon, Karla Kim, Azeb Tadesse Argaw, Yuko Hara, John N. Mariani, Setsu Sawai, Per Flodby, Edward D. Crandall, Zea Borok, Michael V. Sofroniew, Candice Chapouly, Gareth R. John

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Figure 5

Conditional astrocyte Cldn4 inactivation exacerbates the size of inflammatory CNS lesions.

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Conditional astrocyte Cldn4 inactivation exacerbates the size of inflamm...
Cortical AdIL-1 microinjection produces asymptomatic inflammatory lesions characterized by leukocyte (predominantly CD4+ and CD11b+ cell) and humoral factor parenchymal entry, accompanied by reactive astrogliosis and neuronal death. Lesion pathogenesis peaks at 7 dpi and is resolving by 14 dpi. (A–D) Compared with controls, Cldn4 CKO mice display increased AdIL-1 lesion size, as measured by the area of neuronal cell death (NeuN loss), at 7 dpi and 14 dpi (7 dpi: n = 12 CKO, n = 15 WT, P < 0.005; 14 dpi: n = 5 CKO, n = 8 WT, P < 0.05, 2-tailed t test). Scale bars: 300 μm. (E–H) At 7 dpi, lesions of Cldn4 CKO mice have increased numbers of CD4+ lymphocytes (n = 10 CKO, n = 10 WT, P < 0.01, 2-tailed t test) (E and F) and level of CD11b+ staining (n = 6 CKO, n = 9 WT, P < 0.005, 2-tailed t test) (G and H). (I and J) At 7 dpi, lesions of Cldn4 CKO mice show increased areas of IgG entry (n = 8 KO, n = 11 WT, P < 0.01, 2-tailed t test). See also Supplemental Figure 3, A–G. *P < 0.05, **P < 0.01.