Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin,Nature Communications

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Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin
Nature Communications ( IF 14.7 ) Pub Date : 2022-11-02 , DOI: 10.1038/s41467-022-34412-4
Hyosung Kim ₁ , Kun Leng _{2,

3,

4} , Jinhee Park ₅ , Alexander G Sorets ₆ , Suil Kim ₇ , Alena Shostak ₈ , Rebecca J Embalabala ₇ , Kate Mlouk ₇ , Ketaki A Katdare ₇ , Indigo V L Rose ₂ , Sarah M Sturgeon ₁ , Emma H Neal ₁ , Yan Ao ₉ , Shinong Wang ₉ , Michael V Sofroniew ₉ , Jonathan M Brunger ₆ , Douglas G McMahon _{7,

10} , Matthew S Schrag _{7,

8,

11} , Martin Kampmann _{2,

12,

13,

14} , Ethan S Lippmann _{1,

6,

7,

8,

11}

Affiliation

Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.

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.

中文翻译：

反应性星形胶质细胞通过 TNF-STAT3 信号轴和 α1-抗胰凝乳蛋白酶的分泌在血脑屏障模型中转导炎症

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。星形胶质细胞向反应状态的病理转变可能对 BBB 功能有保护作用，也可能有害。在这里，使用人类诱导多能干细胞（iPSC）衍生的 BBB 共培养模型，我们发现肿瘤坏死因子（TNF）将星形胶质细胞转变为炎症反应状态，通过激活 STAT3 和增加 SERPINA3 的表达导致 BBB 功能障碍，它编码α1-抗胰凝乳蛋白酶（α1ACT）。为了将这些发现结合起来，我们将星形细胞 STAT3 激活与死后人体组织中的血管炎症相关联。此外，在鼠脑器官培养物中，星形胶质细胞特异性沉默Serpina3n可减少 TNF 攻击后的血管炎症。最后，在离体外植体培养物和体内用重组 Serpina3n 处理足以诱导 BBB 功能障碍相关的分子变化。总体而言，我们的结果将 TNF-STAT3-α1ACT 信号轴定义为导致 BBB 功能障碍的炎症反应性星形胶质细胞特征的驱动因素。

更新日期：2022-11-03

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