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

• DOI: 10.1038/s41467-022-34412-4
• Publication Date: 2022-11-02T20:29:15Z
• Authors: Hyosung Kim; Kun Leng; Jinhee Park; Alexander G. Sorets; Suil Kim; Alena Shostak; Rebecca J. Embala...; 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; Ethan S. Lippmann
• Keywords: Alpha (finance)

Abstract Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation astrocytes to reactive states can be protective or harmful BBB Here, using a human induced pluripotent stem cell (iPSC)-derived co-culture model, we show tumor necrosis factor (TNF) transitions an inflammatory state causes dysfunction through activation STAT3 and increased expression SERPINA3 , which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, correlated astrocytic vascular inflammation in postmortem tissue. Further, murine brain organotypic cultures, astrocyte-specific silencing Serpina3n reduced after TNF challenge. Last, treatment with recombinant both ex vivo explant cultures was sufficient induce dysfunction-related molecular changes. Overall, our results define TNF-STAT3-α1ACT signaling axis as driver astrocyte signature contributes dysfunction.