Programmed death of macrophages in atherosclerosis: mechanisms and therapeutic targets

Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis — the efficient clearance of dead cells by macrophages — is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies. Macrophages in atherosclerotic plaques can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. In this Review, De Meyer and colleagues describe the various forms of programmed macrophage death in atherosclerosis and the potential therapeutic implications. Key points Programmed death of macrophages, including apoptosis, necroptosis, pyroptosis and ferroptosis, has a role in atherogenesis and vulnerable plaque formation. A balanced interplay exists between these forms of cell death; inhibiting one form can result in the activation of another. Both invasive and non-invasive techniques can identify plaques that might benefit from therapy targeting programmed macrophage death, whereas specific cell death-related biomarkers can aid patient selection for treatment. In early atherosclerotic plaques, the selective removal of macrophages via macrophage-specific death could have plaque-stabilizing effects. In advanced atherosclerotic plaques, sufficient capacit