Moreover, using a combination of human and mouse atherosclerosis, we demonstrate that lipid-induced endoplasmic reticulum (ER) stress in atherogenic macrophages triggers activation of the PERK (protein kinase R–like endoplasmic reticulum kinase)–ATF (activating transcription factor) 4 signaling pathway to impair the NET-induced DNase response with consequent accumulation of NETs in advanced atherosclerosis. Here, EIF2AK2 is linked to atherosclerosis.