Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
Nat Commun. 2022 Nov 2;13(1):6581. doi: 10.1038/s41467-022-34412-4.
Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation of astrocytes to reactive states can be protective or harmful to BBB function. Here, using a human induced pluripotent stem cell (iPSC)-derived BBB co-culture model, we show that tumor necrosis factor (TNF) transitions astrocytes to an inflammatory reactive state that causes BBB dysfunction through activation of STAT3 and increased expression of SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, we correlated astrocytic STAT3 activation to vascular inflammation in postmortem human tissue. Further, in murine brain organotypic cultures, astrocyte-specific silencing of Serpina3n reduced vascular inflammation after TNF challenge. Last, treatment with recombinant Serpina3n in both ex vivo explant cultures and in vivo was sufficient to induce BBB dysfunction-related molecular changes. Overall, our results define the TNF-STAT3-α1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.
星形胶质细胞是支持血脑屏障 (BBB) 功能的神经血管单元的关键组成部分。星形胶质细胞病理性转化为反应性状态可能对 BBB 功能有保护作用，也可能有害。在这里，我们使用人诱导多能干细胞 (iPSC) 衍生的 BBB 共培养模型表明，肿瘤坏死因子 (TNF) 将星形胶质细胞转化为炎症反应性状态，通过激活 STAT3 和增加编码α1-抗胰蛋白酶 (α1ACT) 的 SERPINA3 的表达导致 BBB 功能障碍。为了使这些发现具有背景意义，我们将星形胶质细胞 STAT3 的激活与死后人类组织中的血管炎症相关联。此外，在鼠类脑器官型培养物中，TNF 挑战后，星形胶质细胞特异性沉默 Serpina3n 可减少血管炎症。最后，在离体培养物和体内使用重组 Serpina3n 治疗足以诱导 BBB 功能障碍相关的分子变化。总的来说，我们的结果定义了 TNF-STAT3-α1ACT 信号轴作为炎症反应性星形胶质细胞特征的驱动因素，该特征导致 BBB 功能障碍。
