Astrocytic tight junctions control inflammatory CNS lesion pathogenesis
Astrocytic tight junctions control inflammatory CNS lesion pathogenesis
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DOI：
10.1172/jci91301
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发表时间：
2017-08-01
影响因子：
15.9
通讯作者：
John, Gareth R.
中科院分区：
文献类型：
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作者：
Horng, Sam;Therattil, Anthony;John, Gareth R.
炎症性CNS疾病如多发性硬化症（MS）中的病变和神经功能障碍是由白细胞和体液因子从脉管系统移位引起的，首先穿过内皮血脑屏障（BBB），然后穿过星形胶质细胞界膜（GL）。由反应性星形胶质细胞分泌的因子通过破坏内皮紧密连接（TJ）打开BBB，但控制穿过GL的机制尚不清楚。在这里，我们报告说，在炎症性病变，第二个屏障组成的反应性星形胶质细胞TJ的claudin 1（CLDN 1），CLDN 4，和连接粘附分子A（JAM-A）亚基诱导的GL。在人类共培养模型中，CLDN 4缺陷型星形胶质细胞无法控制淋巴细胞分离。在CNS炎症和MS模型中，具有星形胶质细胞特异性Cldn 4缺失的小鼠显示出加重的白细胞和体液浸润、神经病理学、运动残疾和死亡率。这些发现确定了GL处CNS进入的第二个可诱导屏障。这种屏障在炎性CNS疾病中可能是治疗靶向的。
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.