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

Inflammation of brain endothelial cells is seen in neurodegenerative conditions and in aging. Here the authors examine the role of astrocytes in blood brain barrier function using an iPSC-derived cell co-culture model. 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 (alpha 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-alpha 1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.

Automated summary

In this study, the authors used an iPSC-derived cell co-culture model to investigate the role of astrocytes in blood-brain barrier function. They found that tumor necrosis factor (TNF) could induce inflammatory reactive state in astrocytes, leading to blood-brain barrier dysfunction through STAT3 activation and increased expression of SERPINA3. Further experiments in murine brain organotypic cultures and in vivo demonstrated that silencing Serpina3n could reduce vascular inflammation and treatment with recombinant Serpina3n induced BBB dysfunction-related molecular changes. Overall, the results of this study highlight the importance of the TNF-STAT3-alpha 1ACT signaling axis in the inflammatory reactive astrocyte signature that contributes to BBB dysfunction.