Related Experiment Video
Updated: Jun 26, 2026
Isolation and Flow Cytometric Assessment of Neuroimmune Interactions in a Mini-Stroke Murine Model
Published on: June 20, 2025
The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial
Chen Zhang1, Jie An, Dudley K Strickland
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
Microglia are the immune cells of the central nervous system (CNS) that become activated in response to pathological situations such as cerebral ischemia. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in the intravascular space and the CNS. The low-density lipoprotein receptor-related protein 1 (LRP1) is a member of the low-density lipoprotein receptor gene family found in neurons, astrocytes, and microglia. The present study investigated whether the interaction between tPA and microglial LRP1 plays a role in cerebral ischemia-induced microglial activation. We found that middle cerebral artery occlusion (MCAO) induces microglial activation in both wild-type and plasminogen-deficient (Plg(-/-)) mice. In contrast, MCAO-induced microglial activation is significantly decreased in tPA-deficient (tPA(-/-)) mice and in mice that lack LRP1 in microglial cells (macLRP(-)). We observed a significant increase in microglial activation when tPA(-/-) mice received treatment with murine tPA after MCAO. In contrast, treatment of macLRP(-) mice with tPA did not have an effect on the extent of microglial activation. Finally, both the volume of the ischemic lesion as well as inducible nitric oxide synthase production were significantly decreased in macLRP(-) mice and macLRP(-) microglia. In summary, our results indicate that the interaction between tPA and LRP1 induces microglial activation with the generation of an inflammatory response in the ischemic brain, suggesting a cytokine-like role for tPA in the CNS.
Insights
Tissue-type plasminogen activator (tPA) binding to microglial low-density lipoprotein receptor-related protein 1 (LRP1) drives brain inflammation after stroke. Blocking this interaction reduces microglial activation and lesion size in ischemic stroke models.
Area of Science:
- Neuroscience
- Immunology
- Cerebrovascular Biology
Background:
- Microglia are central nervous system immune cells activated by pathologies like cerebral ischemia.
- Tissue-type plasminogen activator (tPA) and low-density lipoprotein receptor-related protein 1 (LRP1) are present in the CNS.
- LRP1 is expressed in microglia, neurons, and astrocytes.
Purpose of the Study:
- To investigate the role of the interaction between tPA and microglial LRP1 in cerebral ischemia-induced microglial activation.
- To determine the impact of this interaction on ischemic brain injury and inflammation.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in wild-type, plasminogen-deficient, tPA-deficient, and microglial LRP1-deficient (macLRP(-)) mice.
- Administration of tPA to tPA-deficient and macLRP(-) mice post-MCAO.
- Assessment of microglial activation, ischemic lesion volume, and inducible nitric oxide synthase (iNOS) production.
Main Results:
- MCAO induced microglial activation in wild-type and Plg(-/-) mice.
- MCAO-induced microglial activation was significantly reduced in tPA(-/-) and macLRP(-) mice.
- tPA treatment increased microglial activation in tPA(-/-) mice but not in macLRP(-) mice.
- macLRP(-) mice exhibited reduced ischemic lesion volume and iNOS production.
Conclusions:
- The interaction between tPA and microglial LRP1 is a key driver of microglial activation and inflammatory response in the ischemic brain.
- tPA may act as a cytokine-like molecule in the CNS.
- Targeting the tPA-LRP1 interaction could be a therapeutic strategy for ischemic stroke.
