Depletion of BIS in astrocytes aggravates reactive gliosis following photothrombotic brain injury

BIS (Bcl-2-interacting cell death suppressor, or BAG-3), is a multifunctional co-chaperone that maintains protein quality control via autophagy and proteostasis. Following the central nervous system (CNS) injury, BIS expression is markedly upregulated in reactive astrocytes, suggesting a regulatory role of reactive astrogliosis. To investigate this, we generated astrocyte-specific BIS knockout (BIS-aKO) mice for the first time. While BIS-aKO mice exhibited normal growth and survival, the injury-induced upregulation of BIS expression was abolished in reactive astrocytes following excitotoxic injury. Using a photothrombotic stroke model, we found that astrocytic BIS deficiency resulted in significantly increased GFAP expression in scar-forming astrocytes at the infarct border and altered morphology in the peri-infarct region. Furthermore, we observed increased infiltration of amoeboid Iba1-positive cells in the astroglial scar, indicating enhanced neuroinflammation. Correlative light-and electron-microscopy following both stroke and stab wound injury revealed BIS-aKO astrocytes exhibited a greater density of intermediate filament filling in their soma and processes, along with relatively fewer cytoplasmic organelles, such as mitochondria. Collectively, these findings highlight a previously unrecognized role of BIS in modulating reactive gliosis during brain injury and our model provides a valuable tool for investigating the astrocyte-specific functions of BIS in CNS pathophysiology.