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08.08.2024 10:00
Stroke: Inflammation, second stage
An international team of scientists led by the LMU Hospital has carried out detailed research into why the frequently recurring strokes occur: genetic material (DNA) released from cells leads to an inflammatory reaction throughout the body after the first event, which also leads to a worsening of the arteriosclerotic vascular deposits and thus to renewed vascular occlusions – a vicious circle. The researchers led by Prof. Arthur Liesz from the Institute for Stroke and Dementia Research are therefore proposing a new therapy based on their new findings: simply break down the cell-free DNA using appropriate drugs (DNases).
Around 200,000 Germans suffer a stroke every year. It is the second most common cause of death – and a major cause of disability in adulthood. Strokes are usually caused by arteriosclerosis, also known colloquially as hardening of the arteries. This process occurs when immune and inflammatory cells migrate into the walls of blood vessels in fatty deposits. A harmful inflammatory reaction builds up in the resulting “plaques”, which become independent, become chronic, lead to calcification and constrictions and block the vessels. What’s more: clots can break off from these “plaques”, travel through the blood and block small vessels in the brain. But why a good ten percent of patients suffer further strokes within days and weeks, even with the best care in hospital, remained unexplained for a long time.
“We have now largely solved this puzzle,” says Arthur Liesz. The basis for this was initially the establishment of a so-called animal model in the mouse. In such models, the organism is modified through targeted genetic interventions. In this case, recurring strokes from arteriosclerotic plaques can be recreated, as in humans, in order to study the processes involved.
It was shown that in the early phase after a stroke, an inflammatory reaction occurs throughout the body – even though there is no infection. The researchers were able to determine that the cause is cell-free DNA in the blood, which is released from cell debris. This causes inflammation, which also causes arteriosclerosis to progress rapidly, because “this cell-free DNA activates the AIM2 inflammasome in certain immune cells,” says Arthur Liesz. An inflammasome is a whole complex of proteins in inflammatory cells that leads to the massive production of the messenger substance interleukin-1. This messenger substance spreads through the blood throughout the body and has a particular effect on tissue that is already inflamed – such as arteriosclerotic vessels. This in turn destabilizes high-risk plaques, which rupture and release clots, leading to further strokes.
With their knowledge, the researchers started a therapy on the mice after the first stroke: by administering so-called DNases – enzymes that destroy DNA – immediately after the first stroke, the entire fatal process can be stopped. “With this treatment, we have reduced the rate of recurrent strokes in our animal model by up to 80 percent,” says Arthur Liesz. The DNA in cells remains unaffected by this treatment because DNases cannot penetrate cells. The study results have now been published in the renowned scientific journal “Nature” and, if confirmed in humans, could lead to improved stroke therapy.
The impressive success in animal testing has motivated the researchers to plan a clinical trial, which has already been approved. According to Liesz, it is expected to begin in 2025 at several clinics in Germany.
Scientific contacts:
Prof. Dr. Arthur Liesz
Institute for Stroke and Dementia Research (ISD)
LMU Hospital Munich
Campus Grosshadern
Tel: +49 89 4400-46169
E-Mail: [email protected]
Original publication:
Cao, J., Roth, S., Zhang, S. Liesz, A. et al. DNA-sensing inflammasomes cause recurrent atherosclerotic stroke. Nature (2024).
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