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

Hyosung Kim, Kun Leng, Jinhee Park, Alexander G. Sorets, Suil Kim, Alena Shostak, Rebecca J. Embalabala, Kate Mlouk, Ketaki A. Katdare, Indigo V. L. Rose, Sarah M. Sturgeon, Emma H. Neal, Yan Ao, Shinong Wang, Michael V. Sofroniew, Jonathan M. Brunger, Douglas G. McMahon, Matthew S. Schrag, Martin Kampmann and Ethan S. Lippmann ()
Additional contact information
Hyosung Kim: Vanderbilt University
Kun Leng: University of California, San Francisco
Jinhee Park: Vanderbilt University
Alexander G. Sorets: Vanderbilt University
Suil Kim: Vanderbilt University
Alena Shostak: Vanderbilt University Medical Center
Rebecca J. Embalabala: Vanderbilt University
Kate Mlouk: Vanderbilt University
Ketaki A. Katdare: Vanderbilt University
Indigo V. L. Rose: University of California, San Francisco
Sarah M. Sturgeon: Vanderbilt University
Emma H. Neal: Vanderbilt University
Yan Ao: University of California, Los Angeles
Shinong Wang: University of California, Los Angeles
Michael V. Sofroniew: University of California, Los Angeles
Jonathan M. Brunger: Vanderbilt University
Douglas G. McMahon: Vanderbilt University
Matthew S. Schrag: Vanderbilt University
Martin Kampmann: University of California, San Francisco
Ethan S. Lippmann: Vanderbilt University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34412-4

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