ArticleJournal of neuroinflammation2026
Astrocytic CCL5 orchestrates CCR5-positive neuronal necroptosis in subarachnoid hemorrhage.
Article in Journal of neuroinflammation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Treg cells protect astrocytes from ferroptosis after subarachnoid hemorrhage by activating the HIF-1α/Hmox1 pathway.Frontiers in immunology · 2026Article
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12 authors.
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Abstract
backgroundEarly 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.
methodsUsing 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.
resultsWe 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.
conclusionOur 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.
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