Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis

Abstract

Efficient clearance of apoptotic cells, termed efferocytosis, critically regulates normal homeostasis whereas defective uptake of apoptotic cells results in chronic and non-resolving inflammatory diseases, such as advanced atherosclerosis. Monocyte-derived macrophages recruited into developing atherosclerotic lesions initially display efficient efferocytosis and temper inflammatory responses, processes that restrict plaque progression. However, during the course of plaque development, macrophages undergo cellular reprogramming that reduces efferocytic capacity, which results in post-apoptotic necrosis of apoptotic cells and inflammation. Furthermore, defective efferocytosis in advanced atherosclerosis is a major driver of necrotic core formation, which can trigger plaque rupture and acute thrombotic cardiovascular events. In this review, we discuss the molecular and cellular mechanisms that regulate efferocytosis, how efferocytosis promotes the resolution of inflammation, and how defective efferocytosis leads to the formation of clinically dangerous atherosclerotic plaques.

Keywords: atherosclerosis; efferocytosis; inflammation resolution; macrophages; post-apoptotic necrosis.

Figure 1

Mechanisms of efferocytosis. (A) Macrophages interact with phosphatidylserine (PtdSer) externalized on apoptotic cells either directly or indirectly, through bridging molecules. Many PtdSer receptors stimulate ELMO–DOCK180 interactions to activate Rac1 and polymerize actin around the phagosome. Simultaneously, macrophages trigger Drp1-mediated mitochondrial fission to drive calcium-dependent vesicular trafficking. Once internalized, autophagic machinery is used to conjugate lipids to LC3 bound to phagosomes, which drives phagolysosomal fusion and subsequent apoptotic cell degradation. (B) In pathological settings such as advanced atherosclerosis, one or more of these processes can become defective, leading to inefficient clearance of apoptotic cells and subsequent necrosis and inflammation. For example, in advanced atherosclerosis, apoptotic cells can inappropriately express the “don’t eat-me” signal CD47, or cell-surface receptors can get proteolytically cleaved, such as with MerTK.