Frontiers in neuroscience · 2026
A NET-competent neutrophil subpopulation drives early brain injury after subarachnoid hemorrhage.
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Wang Kaikai, Liu Changming, Chu Haifeng, Huang Yi, Qiu Guangmin, Liu Yuchun
Аннотация
INTRODUCTION: Early brain injury (EBI) following subarachnoid hemorrhage (SAH) critically determines neurological outcomes, yet the cellular drivers remain unclear.
METHODS: To systematically dissect acute pathogenic programs, we performed single-cell RNAsequencing of CD45+ immune cells isolated from a mouse model of SAH, coupled with weighted gene co-expression network analysis (WGCNA).
RESULTS: This revealed a 24-h-specific injury module enriched for inflammatory and myeloid-related pathways. Mapping this module onto the single-cell landscape identified neutrophils as the principal cellular mediators. High-resolution subclustering further defined a distinct neutrophil subset, N_04, as the primary carrier of the 24-h pathogenic signature. N_04 is transcriptionally primed for Neutrophil Extracellular Trap (NET) formation, with key effectors including Padi4, Mmp8, and Lcn2, and spatial mapping localized N_04 to regions adjacent to the puncture site. Transcriptional regulatory analysis identified Padi4, Nfe2, and Cebpe as central nodes sustaining N_04 effector identity, while in vivo Padi4 deficiency or NET degradation markedly alleviated neurological deficits. Pseudotime and computational perturbation analyses indicated that N_04 represents a terminal effector state orchestrating hyper-inflammatory, degranulation, and stress-response programs. Intercellular communication modeling further positioned N_04 as a signaling hub, mediating bidirectional crosstalk with macrophages via Cxcl, Ccl, and APP pathways.
DISCUSSION: Collectively, these findings define a NET-competent neutrophil subpopulation as a central driver of acute post-SAH brain injury and nominate Padi4-dependent NETosis as a potential therapeutic target.
METHODS: To systematically dissect acute pathogenic programs, we performed single-cell RNAsequencing of CD45+ immune cells isolated from a mouse model of SAH, coupled with weighted gene co-expression network analysis (WGCNA).
RESULTS: This revealed a 24-h-specific injury module enriched for inflammatory and myeloid-related pathways. Mapping this module onto the single-cell landscape identified neutrophils as the principal cellular mediators. High-resolution subclustering further defined a distinct neutrophil subset, N_04, as the primary carrier of the 24-h pathogenic signature. N_04 is transcriptionally primed for Neutrophil Extracellular Trap (NET) formation, with key effectors including Padi4, Mmp8, and Lcn2, and spatial mapping localized N_04 to regions adjacent to the puncture site. Transcriptional regulatory analysis identified Padi4, Nfe2, and Cebpe as central nodes sustaining N_04 effector identity, while in vivo Padi4 deficiency or NET degradation markedly alleviated neurological deficits. Pseudotime and computational perturbation analyses indicated that N_04 represents a terminal effector state orchestrating hyper-inflammatory, degranulation, and stress-response programs. Intercellular communication modeling further positioned N_04 as a signaling hub, mediating bidirectional crosstalk with macrophages via Cxcl, Ccl, and APP pathways.
DISCUSSION: Collectively, these findings define a NET-competent neutrophil subpopulation as a central driver of acute post-SAH brain injury and nominate Padi4-dependent NETosis as a potential therapeutic target.