Contributions
Abstract: 116
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 18 Neurobiology
Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from translocation of leukocytes and humoral factors from the vasculature, across first the endothelial blood-brain barrier (BBB) and then the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJ), but the mechanisms controlling access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier is induced at the GL, composed of reactive astrocyte TJ of claudin-1 (CLDN-1), CLDN-4 and JAM-A subunits. In a human co-culture model, CLDN-4-deficient astrocytes are unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocytic Cldn-4 deletion display exacerbated leukocyte and humoral infiltration, neuropathology, disability and mortality. These findings identify for the first time a second, inducible barrier to CNS entry at the GL, which may be therapeutically targetable in inflammatory CNS disease.
Disclosure:
Candice Chapouly: nothing to disclose
Abstract: 116
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 18 Neurobiology
Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from translocation of leukocytes and humoral factors from the vasculature, across first the endothelial blood-brain barrier (BBB) and then the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJ), but the mechanisms controlling access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier is induced at the GL, composed of reactive astrocyte TJ of claudin-1 (CLDN-1), CLDN-4 and JAM-A subunits. In a human co-culture model, CLDN-4-deficient astrocytes are unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocytic Cldn-4 deletion display exacerbated leukocyte and humoral infiltration, neuropathology, disability and mortality. These findings identify for the first time a second, inducible barrier to CNS entry at the GL, which may be therapeutically targetable in inflammatory CNS disease.
Disclosure:
Candice Chapouly: nothing to disclose