Astrocyte-Mediated Inflammatory Responses in Traumatic Brain Injury: Mechanisms and Potential Interventions

Haifeng Zhang^1,2*Xian Zhang^1,2Yan Chai²yuhua wang^1,2Jianning Zhang^1,2Xin Chen^1,2*

• ¹Tianjin Medical University General Hospital, Tianjin, China
• ²Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, China

Traumatic brain injury (TBI) remains a leading cause of mortality and long-term disability worldwide, characterized by complex secondary injury cascades that extend beyond the initial mechanical trauma. This comprehensive review critically analyzes the multifaceted role of astrocytes in TBI pathophysiology, with particular emphasis on their transformation from homeostatic maintainers to crucial neuroinflammatory modulators. We systematically examine the temporal sequence of astrocyte activation triggers, encompassing both mechanical transduction pathways and biochemical cascades, including ATP-mediated purinergic signaling, oxidative stress, and damage-associated molecular pattern (DAMP) recognition. The review provides an in-depth analysis of key inflammatory mediators released by activated astrocytes, focusing on the molecular mechanisms underlying the production and regulation of IL-1β, TNF-α, and IL-6, as well as chemokines CCL2 and CXCL10. We present emerging evidence regarding the context-dependent effects of these mediators and their impact on neuroinflammation and recovery. Special attention is devoted to novel findings in astrocytic metabolic reprogramming post-TBI, particularly the Warburg effect and the neuroprotective potential of lactate metabolism, highlighting the complex interplay between cellular energetics and inflammatory responses. Recent technological advances in studying astrocyte heterogeneity are critically evaluated, including multi-omics approaches and optogenetic techniques, which have revolutionized our understanding of astrocyte subpopulations in TBI. We comprehensively assess cutting-edge therapeutic strategies targeting reactive astrocytes, including advanced drug delivery systems, nanotechnology-based approaches, and genetic interventions, while addressing the challenges in clinical translation. The review also examines the potential of astrocyte-related biomarkers in diagnosis and prognosis. By synthesizing current evidence and identifying critical knowledge gaps, we provide a framework for future research directions, emphasizing the need for temporal and spatial precision in therapeutic interventions. This systematic analysis offers valuable insights for both basic researchers and clinicians, potentially guiding the development of more effective TBI treatments through selective modulation of astrocytic responses.