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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


Kim HHyosung , Leng KKun , Park JJinhee , Sorets AGAlexander G , Kim SSuil , Shostak AAlena , Embalabala RJRebecca J , Mlouk KKate , Katdare KAKetaki A , Rose IVLIndigo V L , Sturgeon SMSarah M , Neal EHEmma H , Ao YYan , Wang SShinong , Sofroniew MVMichael V , Brunger JMJonathan M , McMahon DGDouglas G , Schrag MSMatthew S , Kampmann MMartin , Lippmann ESEthan S . Nature communications. 2022 11 02; 13(1). 6581


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.