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Background <p>Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is a major determinant of poor outcomes, yet its molecular mechanisms remain incompletely understood. Neuroinflammation and neuronal death are key pathological features, but the specific signaling pathways linking glial activation to neuronal demise are unclear.</p> Methods <p>Using a murine pre-chiasmatic SAH model, we employed CCR5 knockout mice, astrocyte-specific <i>Ccl5</i> knockdown (via AAV-GFAP-shRNA), pharmacological CCR5 inhibition (Maraviroc), and recombinant CCL5 (rCCL5) administration. Neurological function was assessed. Molecular pathways were examined by qPCR, immunofluorescence, Western blot, and ELISA. The clinical relevance was evaluated in cerebrospinal fluid (CSF) from SAH patients.</p> Results <p>We identified a significant upregulation of CCR5, predominantly in hippocampal neurons, after SAH. Its genetic or pharmacological inhibition attenuated neuronal necroptosis, preserved synaptic integrity, and improved neurobehavioral outcomes. We further demonstrated that the CCR5 ligand CCL5 was primarily released by activated astrocytes. CCR5 ablation reversed the neurotoxicity-exacerbating effect of exogenous rCCL5. Mechanistically, the CCL5/CCR5 axis triggered NF-κB activation, leading to TNF-α/IL-1β production and subsequent p-RIPK3/p-MLKL-mediated neuronal necroptosis. Critically, CSF levels of CCL5 and CCR5 from 41 SAH patients and 22 controls were associated with disease severity and poor prognosis, underscoring its translational significance.</p> Conclusion <p>Our study unveils that astrocytic CCL5 orchestrates CCR5-dependent neuronal necroptosis via NF-κB/p-RIPK3/p-MLKL signaling, thereby driving EBI after SAH. These findings establish the CCL5/CCR5 axis as a potential therapeutic target for mitigating brain injury and cognitive dysfunction in SAH patients.</p>

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Astrocytic CCL5 orchestrates CCR5-positive neuronal necroptosis in subarachnoid hemorrhage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Ping Chen,
  • Yu-He Jiang,
  • Si-Qi Xue,
  • Ying Wang,
  • Wan-Lan Lin,
  • Meng-Yu Shi,
  • Si-Jun Li,
  • Wei-Wei Sun,
  • Jun-Xin Zhao,
  • De-Zhi Kang,
  • Zu-Cheng Ye,
  • Qing-Song Lin

摘要

Background

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is a major determinant of poor outcomes, yet its molecular mechanisms remain incompletely understood. Neuroinflammation and neuronal death are key pathological features, but the specific signaling pathways linking glial activation to neuronal demise are unclear.

Methods

Using a murine pre-chiasmatic SAH model, we employed CCR5 knockout mice, astrocyte-specific Ccl5 knockdown (via AAV-GFAP-shRNA), pharmacological CCR5 inhibition (Maraviroc), and recombinant CCL5 (rCCL5) administration. Neurological function was assessed. Molecular pathways were examined by qPCR, immunofluorescence, Western blot, and ELISA. The clinical relevance was evaluated in cerebrospinal fluid (CSF) from SAH patients.

Results

We identified a significant upregulation of CCR5, predominantly in hippocampal neurons, after SAH. Its genetic or pharmacological inhibition attenuated neuronal necroptosis, preserved synaptic integrity, and improved neurobehavioral outcomes. We further demonstrated that the CCR5 ligand CCL5 was primarily released by activated astrocytes. CCR5 ablation reversed the neurotoxicity-exacerbating effect of exogenous rCCL5. Mechanistically, the CCL5/CCR5 axis triggered NF-κB activation, leading to TNF-α/IL-1β production and subsequent p-RIPK3/p-MLKL-mediated neuronal necroptosis. Critically, CSF levels of CCL5 and CCR5 from 41 SAH patients and 22 controls were associated with disease severity and poor prognosis, underscoring its translational significance.

Conclusion

Our study unveils that astrocytic CCL5 orchestrates CCR5-dependent neuronal necroptosis via NF-κB/p-RIPK3/p-MLKL signaling, thereby driving EBI after SAH. These findings establish the CCL5/CCR5 axis as a potential therapeutic target for mitigating brain injury and cognitive dysfunction in SAH patients.