Blood-brain barrier genetic disruption leads to protective barrier formation at the Glia Limitans.
Blood-brain barrier genetic disruption leads to protective barrier formation at the Glia Limitans.
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DOI：
10.1371/journal.pbio.3000946
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发表时间：
2020-11
期刊：
影响因子：
9.8
通讯作者：
Chapouly C
中科院分区：
文献类型：
--
作者：
Mora P;Hollier PL;Guimbal S;Abelanet A;Diop A;Cornuault L;Couffinhal T;Horng S;Gadeau AP;Renault MA;Chapouly C
中枢神经系统(CNS)的炎症导致内皮血脑屏障(BBB)开放，并在Glia Limitans处反应性星形胶质细胞之间形成紧密连接屏障。我们推测，中枢神经系统实质可能不仅在神经炎症期间，而且在静息状态下血脑屏障完整性受损时，获得对反应性星形细胞胶质限制因子的保护。先前的研究发现，星形细胞来源的Sonic Hedgehog(SHH)在中枢神经系统炎症性疾病时稳定血脑屏障，而内皮细胞来源的沙漠刺猬(DHH)在静息状态下在BBB处表达。在这里，我们研究了内皮DHH对BBB和Glia Limitans完整性的影响。我们首先确定了DHH在血脑屏障内皮细胞中的表达，然后证明了DHH在实验性自身免疫性脑脊髓炎(EAE)中下调。在诱导缺失内皮DHH的小鼠模型中，我们发现内皮DHH既通过调节叉头盒O1(FoxO1)的转录活性打开血脑屏障，又在Glia Limitans处诱导紧密的连接屏障。我们证实了这种胶质屏障系统与人类多发性硬化症活动性病变的相关性。这些结果为“慢性神经炎性耐受”这一新概念提供了证据，在这一概念中，静息状态下的血脑屏障开放足以刺激神经节界限处的保护性屏障，从而限制随后发生的神经炎性疾病的严重程度。总而言之，BBB的遗传破坏产生了内皮信号，这些信号在静止条件下驱动Glia Limitans的次级屏障的形成，从而对随后的CNS炎症起到保护作用。相互调节的中枢神经系统双屏障系统的概念对多发性硬化症的急性期和慢性期的治疗策略具有重要意义。这项研究揭示了信号分子沙漠刺猬(DHH)在维持血脑屏障紧密性方面的关键作用，并强调了中枢神经系统中依赖于内皮细胞和星形胶质细胞之间的串扰的相互调节的双屏障系统。
Inflammation of the central nervous system (CNS) induces endothelial blood–brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of “chronic neuroinflammatory tolerance” in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology. This study uncovers a critical role for the signaling molecule desert hedgehog (Dhh) in maintaining tightness of the blood-brain barrier and highlights a reciprocally regulated double barrier system in the central nervous system that relies on crosstalk between endothelial cells and astrocytes.
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DOI：
10.1084/jem.20102010
发表时间：
2011-02-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cruz-Orengo L;Holman DW;Dorsey D;Zhou L;Zhang P;Wright M;McCandless EE;Patel JR;Luker GD;Littman DR;Russell JH;Klein RS
通讯作者：
Klein RS
影响因子：
6.6
作者：
Chacko AM;Li C;Pryma DA;Brem S;Coukos G;Muzykantov V
通讯作者：
Muzykantov V
影响因子：
15.9
作者：
Horng, Sam;Therattil, Anthony;John, Gareth R.
通讯作者：
John, Gareth R.
DOI：
10.1073/pnas.0808698106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Argaw, Azeb Tadesse;Gurfein, Blake T.;John, Gareth R.
通讯作者：
John, Gareth R.
影响因子：
3.8
作者：
Hewitt, Kyle J.;Agarwal, Rachana;Morin, Patrice J.
通讯作者：
Morin, Patrice J.