Inflammation and net-like protein structures in cerebral cavernous malformations


In the condition known as cavernoma, lesions arise in a cluster of blood vessels in the brain, spinal cord or retina. Researchers at IGP now show in a new study that white blood cells and protein structures associated with the immune response infiltrate the vessel lesions. The findings support that inflammation has a role in the development of cavernoma and indicate a potential biomarker for the disease.  

The vascular lesions, or blood-vessel malformations, that appear in a cerebral cavernoma – also known as a cerebral cavernous malformation (CCM) resemble mulberries. They bleed easily, which may cause epileptic attack, neurological problems and stroke. The condition is due to genetic mutations that may be inherited or occur spontaneously, and is incurable at present.

Research in recent years has suggested that inflammation is involved in CCM. I the new study, the researchers have examined in detail which immune cells respond in CCM. They could also show for the first time that net-like protein structures called NETs are formed in CCM. NETs (for Neutrophil Extracellular Traps) are made up of cell nuclei and cell structures and are associated with the immune response.

“We have used genetically modified mice where a mutated form of a certain gene results in CCM. We found that neutrophils, a type white blood cell, are the first to be recruited to the vessel lesions in mice with CCM. In addition, we detected NETs both in the brain and circulating in the blood. In mice without CCM we didn’t find any NETs,” says Peetra Magnusson, who has led the study.

NETs normally act as a defense in the body by capturing and destroying intruders such as bacteria. High levels of NETs have previously been shown in cancer patients and they are an important component in COVID. These net-like structures can cause vessel damage and the formation of blood clots. Their role in CCM has not been clarified but when the researchers tested a treatment that degraded the NETs, the CCM-related vessel damages were reduced.

Microscope image of white blood cell releasing NET-like protein structures.
The image shows a white blood cell (magenta) releasing
NET-like protein structures (cyan). The immune cell
was isolated from a mouse with CCM.
Image captured by Maria A. Globisch with support
from the BioVis platform. 

The researchers could also detect NETs in brain tissues from patients with CCM, both the inherited form and the one that occurs spontaneously.

“The presence of NETs in CCM patients indicate that they have a role in the disease also in humans. We hope that future studies will increase the knowledge about the importance of immune cells in disease development and whether NETs can be used as a biomarker for CCM,” says Peetra Magnusson.

The study is a collaboration with researchers in Italy, Finland and the UK. It has been published in the journal Cellular and Molecular Life Sciences.

More information:
Paper in Cellular and Molecular Life Sciences
Peetra Magnusson’s research in Elisabetta Dejana’s group

Last modified: 2022-01-26