Pathological Roles of Astrocytes in Traumatic Brain Injury

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Abstract
Background: Astrocytes participate in both neuropathological and protective processes following traumatic brain injury (TBI) and undergo various characteristic changes, including phenotypic transformation, transcriptional reprogramming, and functional diversification. Methods: A comprehensive literature review was conducted in PubMed using key terms “astrocytes” and “traumatic brain injury”, and we integrated this existing evidence from transcriptomic analyses to mechanistic studies to elucidate the role and underlying mechanisms of astrocytes in TBI pathophysiology. Results: Transcriptomic analyses reveal distinct astrocyte phenotypes: neurotoxic A1 astrocytes and neuroprotective A2 astrocytes. Beyond this binary framework, single‐cell studies have identified intermediate astrocyte states, underscoring the need for more nuanced functional profiling. TBI triggers astrocyte activation via classic signaling pathways in response to mechanical stress, damage‐associated molecular patterns (DAMPs), and cytokines. These pathways—TLR4/NF‐κB, JAK/STAT3, and MAPK—form an interactive signaling network, enabling astrocytes to integrate diverse injury signals into coordinated responses that drive subsequent pathological effects. Dysregulation of astrocytic ion channels and transporters disrupts ionic homeostasis, exacerbating cytotoxic and vasogenic edema. Mitochondrial dysfunction and reactive oxygen species overproduction further amplify neuronal damage through lipid peroxidation and excitotoxicity. Interactions between astrocytes and microglia, macrophages, and endothelial cells promote neuroinflammation, blood–brain barrier disruption, synaptic and axonal dysfunction, and neuronal apoptosis via mediators such as matrix metalloproteinases, vascular endothelial growth factor, and adhesion molecules. Additionally, reactive astrocytes inhibit neural regeneration through glial scar formation and secretion of inhibitory molecules. Conclusions: By combining mechanistic studies with translational perspectives, this review highlights that astrocytes act as central mediators of secondary injury and repair in TBI pathology. Given the context‐dependent nature of astrocyte signaling, future therapeutic strategies should aim to reprogram astrocyte responses with temporal and cell‐type precision rather than pursuing broad inhibition. Also, targeting astrocyte‐specific pathways, such as the TLR4 and NF‐κB pathways, may mitigate secondary injury and improve outcomes. This underscores the therapeutic potential of modulating astrocyte responses in the treatment of TBI.
Funding Information
  • National Natural Science Foundation of China (82171283)
  • National Natural Science Foundation of China (82501642)
  • National Natural Science Foundation of China (82471318)
  • National Natural Science Foundation of China (82171292)

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