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<p>Diabetic ischemic stroke leads to more severe brain damage. While the urokinase-type plasminogen activator receptor (PLAUR) is implicated in inflammation and cell migration, its precise role in diabetic stroke remains unclear. A streptozotocin-induced diabetic tMCAO mouse model was employed to simulate diabetic ischemic stroke. PLAUR expressions in mouse brain tissues were analyzed using microarray, Western blot, and immunofluorescence. PLAUR mRNA expression in endothelial cells (bEnd.3) was analyzed by RT-qPCR. We assessed cerebral infarct volume, brain water content, neurological deficits, and BBB integrity. Neutrophil infiltration (flow cytometry), inflammatory mediators, microglial polarization, and metabolic reprogramming (glycolytic proteins, ECAR/OCR) were investigated in vivo and in vitro. To test whether neutrophils are essential for PLAUR-mediated injury, we performed neutrophil depletion experiments using anti-Ly6G antibody, alone or combined with PLAUR knockdown. Neutrophil extracellular trap (NET) formation (CitH3 expression) and its impact on endothelial permeability and microglial polarization were also examined. PLAUR was significantly upregulated in the brains of diabetic stroke mice, particularly in microglia. PLAUR knockdown resulted in smaller infarct volumes, improved functional recovery, and maintained BBB integrity by restoring tight junction proteins. PLAUR knockdown was associated with reduced neutrophil infiltration, decreased pro-inflammatory mediator (MPO, MMP3) and attenuated pro-inflammatory M1 microglial polarization. PLAUR silencing also reduced NETosis in vivo and in isolated neutrophils. Neutrophil depletion alone significantly reduced infarct volume, improved neurological outcomes, and restored tight junction proteins; notably, PLAUR knockdown provided no additional benefit when neutrophils were already depleted, indicating that neutrophils are essential downstream effectors of PLAUR-mediated injury. Furthermore, PLAUR knockdown reversed the glycolytic shift in microglia. PLAUR is upregulated in diabetic ischemic stroke and its knockdown is associated with reduced neuroinflammation, preserved BBB integrity, decreased neutrophil infiltration, attenuated NETosis, and shifts in microglial polarization and metabolism. Therefore, targeting PLAUR represents a promising therapeutic strategy for attenuating brain injury in diabetic stroke.</p>

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PLAUR Exacerbates Neuroinflammation in Diabetic Ischemic Stroke by Driving Neutrophil-Mediated Blood-Brain Barrier Disruption and Reprogramming Microglial Metabolism

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Si-qi Ma,
  • Long Wang,
  • Xu Liu,
  • Yi-ning Yue,
  • Si-nian Wang,
  • Yuan Feng,
  • Shuhui Xin,
  • Pu Zhu,
  • Feng-sheng Li,
  • Shi-min Yin

摘要

Diabetic ischemic stroke leads to more severe brain damage. While the urokinase-type plasminogen activator receptor (PLAUR) is implicated in inflammation and cell migration, its precise role in diabetic stroke remains unclear. A streptozotocin-induced diabetic tMCAO mouse model was employed to simulate diabetic ischemic stroke. PLAUR expressions in mouse brain tissues were analyzed using microarray, Western blot, and immunofluorescence. PLAUR mRNA expression in endothelial cells (bEnd.3) was analyzed by RT-qPCR. We assessed cerebral infarct volume, brain water content, neurological deficits, and BBB integrity. Neutrophil infiltration (flow cytometry), inflammatory mediators, microglial polarization, and metabolic reprogramming (glycolytic proteins, ECAR/OCR) were investigated in vivo and in vitro. To test whether neutrophils are essential for PLAUR-mediated injury, we performed neutrophil depletion experiments using anti-Ly6G antibody, alone or combined with PLAUR knockdown. Neutrophil extracellular trap (NET) formation (CitH3 expression) and its impact on endothelial permeability and microglial polarization were also examined. PLAUR was significantly upregulated in the brains of diabetic stroke mice, particularly in microglia. PLAUR knockdown resulted in smaller infarct volumes, improved functional recovery, and maintained BBB integrity by restoring tight junction proteins. PLAUR knockdown was associated with reduced neutrophil infiltration, decreased pro-inflammatory mediator (MPO, MMP3) and attenuated pro-inflammatory M1 microglial polarization. PLAUR silencing also reduced NETosis in vivo and in isolated neutrophils. Neutrophil depletion alone significantly reduced infarct volume, improved neurological outcomes, and restored tight junction proteins; notably, PLAUR knockdown provided no additional benefit when neutrophils were already depleted, indicating that neutrophils are essential downstream effectors of PLAUR-mediated injury. Furthermore, PLAUR knockdown reversed the glycolytic shift in microglia. PLAUR is upregulated in diabetic ischemic stroke and its knockdown is associated with reduced neuroinflammation, preserved BBB integrity, decreased neutrophil infiltration, attenuated NETosis, and shifts in microglial polarization and metabolism. Therefore, targeting PLAUR represents a promising therapeutic strategy for attenuating brain injury in diabetic stroke.