Astrocytic CCL5 orchestrates CCR5-positive neuronal necroptosis in subarachnoid hemorrhage
..." 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"...
https://pubmed.ncbi.nlm.nih.gov/41639749/
..." 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"...
https://pubmed.ncbi.nlm.nih.gov/41639749/
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