Interplay between efferocytosis and atherosclerosis

In an adult human, billions of cells die and turn over daily. During this process, many apoptotic cells are produced and subsequently cleared by phagocytes - a process termed efferocytosis, which plays a critical role in tissue homeostasis. Efferocytosis is an important mechanism in the control of inflammatory processes. Efficient efferocytosis inhibits accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. During efferocytosis, mitochondrial fission and the oxidative stress process are linked through reactive oxygen species production and oxidative stress control. Autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis by activated inflammatory cells, particularly neutrophils and macrophages. Autophagy in neutrophils is activated by phagocytosis of pathogens or activation of pattern recognition receptors. Autophagy is essential for major neutrophil functions, including degranulation, reactive oxygen species production, oxidative stress and release of neutrophil extracellular cytokines. Failed efferocytosis is a key mechanism driving the development and progression of chronic inflammatory diseases, including atherosclerosis, cardiometabolic pathology, neurodegenerative disease and cancer. Impairment of efferocytosis in apoptotic macrophages is a determinant of atherosclerosis severity and the vulnerability of plaques to rupture. Recent results suggest that inhibition of efferocytosis in the protection of the myocardium results in reduced infiltration of reparatory macrophages into the tissue, in association with oxidative stress reduction. Activated macrophages play a central role in the development and resolution of inflammation. The resolution of inflammation through efferocytosis is an endogenous process that protects host tissues from prolonged or excessive inflammation. Accordingly, therapeutic strategies that ameliorate efferocytosis control would be predicted to dampen inflammation and improve resolution. Thus, therapies targeting efferocytosis will provide a new means of treating and preventing cardiovascular and metabolic diseases involving the chronic inflammatory state.