BACKGROUND AND AIMS

Cell death plays a central role in atheroma plaque progression and aggravation. This study investigates the role of caspase-8 in regulating macrophage cell death modalities, specifically apoptosis and necroptosis, within atheroma plaques.

METHODS

Bone marrow from caspase-8-deficient ( ) and cohoused wildtype littermates were transplanted in atherosclerosis-prone recipient mice fed with a proatherogenic diet. Aortic plaque development, necrotic core formation, and cell death were analyzed through histological and biochemical assays. investigation of macrophages exposed to atherogenic stimuli assessed the effects of caspase-8 inhibition on apoptotic and necroptotic pathways.

RESULTS

Despite lower plasma cholesterol levels and reduced number of inflammatory monocytes, caspase-8-deficient mice exhibited more pronounced atherosclerotic lesions with enlarged necrotic cores and an increased number of dead cells. , in macrophages exposed to oxidized LDL or oxysterols, the inhibition of caspase-8 revealed a shift from apoptosis to necroptosis as confirmed by increased phosphorylation of MLKL along with decreased cleavage of caspase-3 and -7.

DISCUSSION AND PERSPECTIVES

The study highlights the role of caspase-8 in atherosclerosis in tuning the balance between apoptosis and necroptosis. Caspase-8 inhibition leads to a switch towards necroptosis and accumulation of dead cell corpses that contributes to enhanced plaque severity. These findings suggest that reducing caspase-8-regulated necroptosis and necrosis in macrophages could represent a therapeutic strategy to stabilize plaques and reduce cardiovascular risk.