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Endothelial NLRP3-mediated pyroptosis induces blood-brain barrier and neuronal damage in Huntington's disease models
Jing Cai1, Wenshuang Ji1, Peng Liu2
1Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, PR China.
Abstract:
The NLRP3 inflammasome is primarily expressed and activated in microglial and endothelial cells. Extensive research has been conducted on the activation of NLRP3 inflammasomes by microglial cells leading to pyroptosis. However, there have been no reports on the activation of NLRP3 inflammasomes in brain vascular endothelial cells in patients with Huntington's disease (HD) or HD animal models, leading to blood-brain barrier (BBB) disruption. We herein found that BBB leakage increased and the expression of tight junction proteins significantly decreased after transfecting the mutant Huntingtin protein (mHtt) Q74 plasmid into the mouse brain microvascular endothelial cell line bEnd.3. mHtt promoted the activation of NLRP3 by brain vascular endothelial cells, and increased the expression of the pyroptosis-related proteins. This resulted in a decrease in the expression of the NeuN in the brain of hHTT130 transgenic mice. Furthermore, by downregulating NLRP3 in Q74-transfected bEnd.3 cells or in hHTT130 mouse brain vascular endothelial cells, BBB disruption and endothelial cell pyroptosis were alleviated, the number of surviving neurons was significantly increased. In conclusion, mHtt can activate the NLRP3 inflammasome in brain microvascular endothelial cells to induce endothelial cell pyroptosis, thereby disrupting the function of the BBB, leading to neuronal damage.
Insights
Mutant Huntingtin activates the NLRP3 inflammasome in brain endothelial cells, causing blood-brain barrier dysfunction and neuronal damage in Huntington's disease. Downregulating NLRP3 alleviates these effects.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- The NLRP3 inflammasome is crucial in microglial cells, but its role in brain vascular endothelial cells (BECs) in Huntington's disease (HD) remains unexplored.
- HD is characterized by neurodegeneration, with blood-brain barrier (BBB) disruption contributing to pathology.
Purpose of the Study:
- To investigate the role of NLRP3 inflammasome activation in BECs in HD pathogenesis.
- To determine if mutant Huntingtin (mHtt) induces BBB disruption via NLRP3 inflammasome activation and endothelial cell pyroptosis.
Main Methods:
- Transfection of mouse BECs (bEnd.3) with mutant Huntingtin (mHtt) Q74 plasmid.
- Assessment of BBB leakage and tight junction protein expression.
- Analysis of NLRP3 inflammasome activation and pyroptosis markers.
- Evaluation of NeuN expression in hHTT130 transgenic mice.
- Inhibition of NLRP3 in mHtt-treated cells and HD mouse models.
Main Results:
- mHtt transfection increased BBB leakage and decreased tight junction proteins in bEnd.3 cells.
- mHtt promoted NLRP3 activation and pyroptosis in BECs, leading to decreased neuronal marker NeuN in hHTT130 mice.
- Downregulating NLRP3 ameliorated BBB disruption, reduced endothelial cell pyroptosis, and increased neuronal survival.
Conclusions:
- Mutant Huntingtin activates the NLRP3 inflammasome in brain microvascular endothelial cells.
- This activation induces endothelial cell pyroptosis, leading to BBB dysfunction and subsequent neuronal damage in Huntington's disease.
- Targeting the NLRP3 inflammasome presents a potential therapeutic strategy for HD.
