Abstract
Nature Communications 2022, 13, 6581
Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin
Kim H, Leng K, Park J, Sorets AG, Kim S, Shostak A, Embalabala RJ, Mlouk K, Katdare KA, Rose IVL, Sturgeon SM, Neal EH, Ao Y, Wang S, Sofroniew MV, Brunger JM, McMahon DG, Schrag MS, Kapmann M, Lippmann ES
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 (?1ACT). 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-?1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.