Macrophage DNases Limit Neutrophil Extracellular Trap-Mediated Defective Efferocytosis in Atherosclerosis.

backgroundNeutrophil extracellular traps (NETs) contribute to atherosclerosis progression and are linked to adverse clinical outcomes such as myocardial infarction and stroke. Although the triggers of NET formation in plaques are known, the mechanisms governing DNase-mediated NET clearance and how these are disrupted during atherosclerosis remain unclear. Moreover, the consequences of impaired NET clearance on disease progression are not known.

methodsLow-density lipoprotein receptor knockout (

resultsLack of DNase secretion by macrophages led to accumulation of NETs in local tissues, including atherosclerotic plaques. Persisting NETs in turn promoted cleavage of the efferocytosis receptor MerTK (c-mer proto-oncogene tyrosine kinase), resulting in defective macrophage efferocytosis and increased atherosclerotic plaque necrosis. In vitro screening identified endoplasmic reticulum stress-induced activation of the PERK (protein kinase R-like endoplasmic reticulum kinase)-ATF (activating transcription factor) 4 signaling axis in atherogenic macrophages as a key driver of impaired DNase secretion, leading to delayed NET clearance and their pathological persistence. Treatment of human atherosclerotic plaques and

conclusionsMacrophages play a key role in clearing NETs from tissues. Endoplasmic reticulum stress suppresses macrophage DNase secretion, leading to NET accumulation in atherosclerotic plaques, which triggers efferocytosis impairment and plaque progression. Targeting the PERK-ATF4 axis to restore DNase release and NET clearance represents a promising therapeutic strategy to promote plaque stabilization.