Endothelial NLRP3-mediated pyroptosis induces blood-brain barrier and neuronal damage in Huntington's disease models

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.