Scholarlink

Background <p>Ischemic stroke is a leading cause of adult disability and death, yet recanalization therapies that reopen occluded large arteries benefit only a subset of patients. Stroke patients can experience poor outcomes due to recanalization failure or the no-reflow phenomenon, where inflammation and microvascular obstructions prevent effective reperfusion despite successful large-vessel reopening. We hypothesized that failure of collateral and microcirculatory flow is a critical factor underlying the incongruity between large-vessel recanalization and effective tissue reperfusion. Neutrophils, as early responders to ischemic injury, are prime mediators of microvascular dysfunction. To test this, we investigated whether targeted depletion of neutrophils could preserve microvascular flow, improve perfusion, and attenuate inflammatory responses in stroke.</p> Main body <p>Using a mouse model of middle cerebral artery occlusion, we applied a double-antibody depletion strategy to achieve efficient and specific removal of circulating neutrophils. This multi-modal study integrated high-resolution intravital imaging of cerebral blood flow and cellular dynamics, cytokine assays, transcriptomic profiling, and infarct size measurements. Neutrophil depletion preserved cortical perfusion (~ 30% vs. ~ 60% reduction in untreated mice), reduced capillary stalls, and nearly doubled early post-reperfusion capillary flow (red blood cell flux ~ 72% vs. ~ 33%). Infarct volumes were modestly reduced, with the most pronounced benefit in aged and female cohorts. Transcriptomic profiling revealed broad suppression of neutrophil-driven inflammatory programs (including <i>Il1b</i>, <i>Mmp8</i>, <i>Lcn2</i>, <i>Tlr2</i>, and <i>Cd14</i>), while protective homeostatic signals (such as <i>Mef2c</i>) were maintained and delayed pro-inflammatory activation (<i>Itgam</i>, <i>Txnip</i>, <i>Tlr13</i>) was prevented. Cytokine assays supported a dampened systemic inflammatory response following neutrophil depletion.</p> Conclusions <p>These findings identify neutrophils as central drivers of microvascular failure in acute stroke and support their therapeutic targeting to enhance reperfusion and limit inflammation. The use of a double-antibody depletion strategy underscores both the mechanistic importance of neutrophils and the translational potential of precise immune-modulatory interventions. Our multi-modal approach provides comprehensive insight into immune-vascular interactions after stroke and highlights a translationally relevant strategy for improving outcomes following recanalization therapies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Integrative imaging and transcriptomics implicate neutrophils in microvascular no-reflow after stroke

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

查看全文
  • Sima Abbasi-Habashi,
  • Mike Clarke,
  • Yonglie Ma,
  • Maria Guadalupe C. Real,
  • Gabrielle M. Siegers,
  • Glen C. Jickling,
  • Ian R. Winship

摘要

Background

Ischemic stroke is a leading cause of adult disability and death, yet recanalization therapies that reopen occluded large arteries benefit only a subset of patients. Stroke patients can experience poor outcomes due to recanalization failure or the no-reflow phenomenon, where inflammation and microvascular obstructions prevent effective reperfusion despite successful large-vessel reopening. We hypothesized that failure of collateral and microcirculatory flow is a critical factor underlying the incongruity between large-vessel recanalization and effective tissue reperfusion. Neutrophils, as early responders to ischemic injury, are prime mediators of microvascular dysfunction. To test this, we investigated whether targeted depletion of neutrophils could preserve microvascular flow, improve perfusion, and attenuate inflammatory responses in stroke.

Main body

Using a mouse model of middle cerebral artery occlusion, we applied a double-antibody depletion strategy to achieve efficient and specific removal of circulating neutrophils. This multi-modal study integrated high-resolution intravital imaging of cerebral blood flow and cellular dynamics, cytokine assays, transcriptomic profiling, and infarct size measurements. Neutrophil depletion preserved cortical perfusion (~ 30% vs. ~ 60% reduction in untreated mice), reduced capillary stalls, and nearly doubled early post-reperfusion capillary flow (red blood cell flux ~ 72% vs. ~ 33%). Infarct volumes were modestly reduced, with the most pronounced benefit in aged and female cohorts. Transcriptomic profiling revealed broad suppression of neutrophil-driven inflammatory programs (including Il1b, Mmp8, Lcn2, Tlr2, and Cd14), while protective homeostatic signals (such as Mef2c) were maintained and delayed pro-inflammatory activation (Itgam, Txnip, Tlr13) was prevented. Cytokine assays supported a dampened systemic inflammatory response following neutrophil depletion.

Conclusions

These findings identify neutrophils as central drivers of microvascular failure in acute stroke and support their therapeutic targeting to enhance reperfusion and limit inflammation. The use of a double-antibody depletion strategy underscores both the mechanistic importance of neutrophils and the translational potential of precise immune-modulatory interventions. Our multi-modal approach provides comprehensive insight into immune-vascular interactions after stroke and highlights a translationally relevant strategy for improving outcomes following recanalization therapies.