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<p>Delayed cerebral ischemia (DCI) remains a major cause of poor neurological outcomes following aneurysmal subarachnoid hemorrhage (aSAH), yet its underlying immune mechanisms remain incompletely understood. This study aimed to characterize the peripheral immune profile in patients with ruptured intracranial aneurysms (RIA) and its association with delayed cerebral ischemia (DCI), emphasizing the role of systemic immunity in post-hemorrhagic complications. We prospectively enrolled a cohort of 17 patients diagnosed with ruptured intracranial aneurysms, including 8 who developed DCI and 9 who did not. High-dimensional mass cytometry (CyTOF) was employed to perform immunophenotyping of peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs), using antibody panels targeting lineage, activation, and functional markers. Data were analyzed using FlowSOM clustering and t-SNE for dimensionality reduction. PBMC analysis revealed that patients without DCI exhibited significantly higher frequencies of natural killer (NK) cells, including CD56⁻CD16⁺ and CD56dimCD16⁺ subsets. Conversely, NK cells in DCI patients showed a dysfunctional phenotype with elevated PD-1 expression. Monocyte subsets in the DCI group also demonstrated increased PD-1 levels, indicating systemic immune suppression. Within PMNs, 12 distinct neutrophil subsets were identified, including classical, immature, mature, and senescent phenotypes. Although no significant differences in subset proportions were observed between groups, functional analysis showed that neutrophils from Non-DCI patients expressed higher levels of the proinflammatory cytokine TNF-α across multiple subsets (CD10⁺, CD34⁺, CD86⁺, and CD49d⁺CXCR4⁺). In contrast, the senescent neutrophil subset (CD49d⁺CXCR4⁺) in DCI patients preferentially expressed the anti-inflammatory cytokine IL-10. In conclusion, this exploratory study reveals distinct immune alterations associated with DCI after aSAH, including a PD-1high NK cell phenotype and altered neutrophil polarization. These findings highlight immune dysregulation as a potential contributor to DCI pathophysiology and suggest that NK cell and neutrophil phenotypes warrant further investigation as candidate biomarkers in larger prospective studies. </p>

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High-dimensional immune profiling reveals NK cell dysregulation and neutrophil polarization after aneurysmal subarachnoid hemorrhage in delayed cerebral ischemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Long Ma,
  • Xiaolong Ya,
  • Chenglong Liu,
  • Peicong Ge,
  • Chaofan Zeng,
  • Qiheng He,
  • Hao Li,
  • Qian Zhang,
  • Rong Wang,
  • Yan Zhang,
  • Enshan Feng,
  • Jizong Zhao

摘要

Delayed cerebral ischemia (DCI) remains a major cause of poor neurological outcomes following aneurysmal subarachnoid hemorrhage (aSAH), yet its underlying immune mechanisms remain incompletely understood. This study aimed to characterize the peripheral immune profile in patients with ruptured intracranial aneurysms (RIA) and its association with delayed cerebral ischemia (DCI), emphasizing the role of systemic immunity in post-hemorrhagic complications. We prospectively enrolled a cohort of 17 patients diagnosed with ruptured intracranial aneurysms, including 8 who developed DCI and 9 who did not. High-dimensional mass cytometry (CyTOF) was employed to perform immunophenotyping of peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs), using antibody panels targeting lineage, activation, and functional markers. Data were analyzed using FlowSOM clustering and t-SNE for dimensionality reduction. PBMC analysis revealed that patients without DCI exhibited significantly higher frequencies of natural killer (NK) cells, including CD56⁻CD16⁺ and CD56dimCD16⁺ subsets. Conversely, NK cells in DCI patients showed a dysfunctional phenotype with elevated PD-1 expression. Monocyte subsets in the DCI group also demonstrated increased PD-1 levels, indicating systemic immune suppression. Within PMNs, 12 distinct neutrophil subsets were identified, including classical, immature, mature, and senescent phenotypes. Although no significant differences in subset proportions were observed between groups, functional analysis showed that neutrophils from Non-DCI patients expressed higher levels of the proinflammatory cytokine TNF-α across multiple subsets (CD10⁺, CD34⁺, CD86⁺, and CD49d⁺CXCR4⁺). In contrast, the senescent neutrophil subset (CD49d⁺CXCR4⁺) in DCI patients preferentially expressed the anti-inflammatory cytokine IL-10. In conclusion, this exploratory study reveals distinct immune alterations associated with DCI after aSAH, including a PD-1high NK cell phenotype and altered neutrophil polarization. These findings highlight immune dysregulation as a potential contributor to DCI pathophysiology and suggest that NK cell and neutrophil phenotypes warrant further investigation as candidate biomarkers in larger prospective studies.