Brain endothelial GSDMD activation mediates inflammatory BBB breakdown. (https://pubmed.ncbi.nlm.nih.gov/38632402/)
These scientists wanted to understand how the blood-brain barrier works to protect our brain from infections or harmful substances. They discovered that a protein called GSDMD, when activated by another protein called caspase-11, can cause the blood-brain barrier to break down in response to certain infections. They found that mice deficient in a pathway that helps transfer and internalize harmful substances were able to resist this breakdown.
By looking at individual brain cells and using advanced technology to study them, the scientists found that the cells lining the blood vessels in the brain have a strong response to certain infections. When these cells are exposed to a harmful substance called LPS, they activate GSDMD, leading to the breakdown of the blood-brain barrier.
Through their experiments with mice and genetic analyses, the scientists were able to confirm that GSDMD activation in these brain cells is responsible for the barrier breakdown. They also found that by delivering active GSDMD directly into these cells, they could open the blood-brain barrier without the need for infection.
In a separate experiment using mice that were genetically modified to have a human protein, the scientists showed that an infection with certain bacteria could also disrupt the blood-brain barrier. However, by blocking GSDMD with a special protein called a nanobody, they were able to prevent this breakdown.
Overall, the scientists discovered a new mechanism for how the blood-brain barrier can be disrupted during infections, and they believe that this research could lead to new treatments for diseases of the central nervous system that are associated with problems in the blood-brain barrier.
Wei C., Jiang W., Wang R., Zhong H., He H., Gao X., Zhong S., Yu F., Guo Q., Zhang L., Schiffelers LDJ., Zhou B., Trepel M., Schmidt FI., Luo M., Shao F. Brain endothelial GSDMD activation mediates inflammatory BBB breakdown. Nature. 2024 May;629(8013):893-900. doi: 10.1038/s41586-024-07314-2. Epub 2024 Apr 17.