Research progress on neurovascular and neuroimmune interactions during thrombolysis and reperfusion in acute ischemic stroke
- 1Department of Neurology, Changzheng Hospital, the Second Affiliated Hospital of Naval Medical University
- 2Department of Neurovascular Disease, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University
- 3Department of Clinical Medicine, School of Medicine, Tongji University
Abstract
Acute ischemic stroke (AIS) remains a leading cause of adult mortality and lasting disability worldwide. Although intravenous thrombolysis and mechanical thrombectomy have established the reperfusion era, a substantial proportion of patients fail to achieve favorable functional outcomes because macrovascular recanalization does not guarantee effective perfusion at the tissue level. This review systematically examines the neurovascular unit (NVU) and the expanded neurovascular immune network as integrated frameworks for understanding brain injury following reperfusion. We delineate the temporal cascade of pathophysiological events, beginning with acute ischemic energy failure, excitotoxicity, and innate immune sensing by cerebral microvascular endothelial cells and microglia. We then focus on the reperfusion phase as the critical window of neuroimmune interaction, characterized by reactive oxygen species burst, nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, neutrophil extracellular traps (NETs) formation, and matrix-metalloproteinase (MMP) mediated disruption of the blood-brain-barrier (BBB). The chronological infiltration and phenotypic transitions of peripheral immune cells, including neutrophils, classical monocytes, and T lymphocytes, are analyzed in relation to biphasic dynamics of the BBB and evolving therapeutic time windows. Furthermore, we evaluate translational advances in combination strategies that pair agents with anti-inflammatory properties and thrombolysis, interventions targeting NETs, blood brain barrier protection, and immunomodulation strategies tailored to specific time windows, alongside emerging biomarkers and novel delivery technologies. This review aims to provide a framework grounded in evidence for mechanistic understanding and therapeutic optimization toward comprehensive neurovascular and neuroimmune repair in the reperfusion era. Unless otherwise specified, mechanistic findings cited in this review derive predominantly from experimental rodent models (mainly transient middle cerebral artery occlusion, tMCAO) or in vitro studies, and human evidence is explicitly indicated where available.
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BibTeX
@article{gu2026research,
title = {{Research progress on neurovascular and neuroimmune interactions during thrombolysis and reperfusion in acute ischemic stroke}},
author = {Huanhuan Gu and Yue Chen and Shifei Ye and Meng Du and Huayu Jiang and Yihao Qian and Yibin Fang and Peng Li},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1967545},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1967545/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Research progress on neurovascular and neuroimmune interactions during thrombolysis and reperfusion in acute ischemic stroke
AU - Huanhuan Gu
AU - Yue Chen
AU - Shifei Ye
AU - Meng Du
AU - Huayu Jiang
AU - Yihao Qian
AU - Yibin Fang
AU - Peng Li
PY - 2026
DA - 2026/11/03
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1967545
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1967545/full
AB - Acute ischemic stroke (AIS) remains a leading cause of adult mortality and lasting disability worldwide. Although intravenous thrombolysis and mechanical thrombectomy have established the reperfusion era, a substantial proportion of patients fail to achieve favorable functional outcomes because macrovascular recanalization does not guarantee effective perfusion at the tissue level. This review systematically examines the neurovascular unit (NVU) and the expanded neurovascular immune network as integrated frameworks for understanding brain injury following reperfusion. We delineate the temporal cascade of pathophysiological events, beginning with acute ischemic energy failure, excitotoxicity, and innate immune sensing by cerebral microvascular endothelial cells and microglia. We then focus on the reperfusion phase as the critical window of neuroimmune interaction, characterized by reactive oxygen species burst, nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, neutrophil extracellular traps (NETs) formation, and matrix-metalloproteinase (MMP) mediated disruption of the blood-brain-barrier (BBB). The chronological infiltration and phenotypic transitions of peripheral immune cells, including neutrophils, classical monocytes, and T lymphocytes, are analyzed in relation to biphasic dynamics of the BBB and evolving therapeutic time windows. Furthermore, we evaluate translational advances in combination strategies that pair agents with anti-inflammatory properties and thrombolysis, interventions targeting NETs, blood brain barrier protection, and immunomodulation strategies tailored to specific time windows, alongside emerging biomarkers and novel delivery technologies. This review aims to provide a framework grounded in evidence for mechanistic understanding and therapeutic optimization toward comprehensive neurovascular and neuroimmune repair in the reperfusion era. Unless otherwise specified, mechanistic findings cited in this review derive predominantly from experimental rodent models (mainly transient middle cerebral artery occlusion, tMCAO) or in vitro studies, and human evidence is explicitly indicated where available.
SN - 1664-3224
ER -