Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.
Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.
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DOI：
10.1084/jem.20150165
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发表时间：
2015-09-21
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影响因子：
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通讯作者：
Schwaninger M
中科院分区：
文献类型：
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作者：
Ridder DA;Wenzel J;Müller K;Töllner K;Tong XK;Assmann JC;Stroobants S;Weber T;Niturad C;Fischer L;Lembrich B;Wolburg H;Grand'Maison M;Papadopoulos P;Korpos E;Truchetet F;Rades D;Sorokin LM;Schmidt-Supprian M;Bedell BJ;Pasparakis M;Balschun D;D'Hooge R;Löscher W;Hamel E;Schwaninger M
Ridder等人表明，脑内皮细胞中NF-kB信号传导的一种组分NEMO的缺失导致脑血管通透性增加和内皮细胞死亡，并重现了遗传性疾病色素失禁中观察到的神经症状。NF-κB必需调节因子（NEMO）是NF-κB信号传导的关键组分，其失活突变导致遗传性疾病色素失禁（IP）。这会导致严重的神经系统症状，但大脑参与的机制尚不清楚。在这里，我们表明，选择性删除尼莫或上游激酶Tak 1在脑内皮细胞导致内皮细胞死亡，稀疏的脑微血管，脑灌注不足，破坏血脑屏障（BBB），癫痫发作。TAK 1和NEMO通过激活转录因子NF-κB和稳定紧密连接蛋白occludin来保护BB B。它们还通过减少氧化损伤以NF-κ B非依赖性方式防止脑内皮细胞死亡。我们的数据确定了炎性TAK 1-NEMO信号在保护脑内皮和维持正常脑功能方面的关键功能，从而解释了与IP相关的神经系统症状。
Ridder et al. show that deletion of NEMO, a component of NF-kB signaling, in brain endothelial cells results in increased cerebral vascular permeability and endothelial cell death, and recapitulates the neurological symptoms observed in the genetic disease incontinentia pigmenti. Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood–brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB–independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1–NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP.