DNA-sensing inflammasomes cause recurrent atherosclerotic stroke

Area of Science:

• Cardiovascular Research
• Immunology
• Neuroscience

Background:

• Recurrent stroke risk is high, especially in atherosclerosis patients, with unknown underlying mechanisms.
• Current secondary prevention strategies are insufficient to mitigate early recurrent events.

Purpose of the Study:

• To elucidate the mechanisms driving early recurrent stroke in atherosclerosis.
• To identify novel therapeutic targets for preventing post-stroke recurrence.

Main Methods:

• Utilized a novel mouse model of stroke-induced recurrent ischemia.
• Investigated AIM2 inflammasome activation, cell-free DNA, and neutrophil extracellular traps (NETosis).
• Assessed therapeutic efficacy of DNase treatment and inflammasome inhibition.

Main Results:

• Stroke activates AIM2 inflammasome in atherosclerotic plaques via increased cell-free DNA.
• This leads to plaque destabilization, atherothrombosis, and recurrent stroke.
• Neutrophil NETosis is the primary source of cell-free DNA, which activates AIM2 inflammasome.

Conclusions:

• Identified a novel mechanism linking stroke, cell-free DNA, inflammasome activation, and recurrent events in atherosclerosis.
• Demonstrated therapeutic potential of targeting DNA-mediated inflammasome activation to prevent recurrent stroke.