Mechanisms of continual efferocytosis by macrophages and its role in mitigating atherosclerosis

Abstract

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Rupture-prone atheromas that give rise to myocardial infarction and stroke are characterized by the presence of a necrotic core and a thin fibrous cap. During homeostasis, cellular debris and apoptotic cells are cleared quickly through a process termed “efferocytosis”. However, clearance of apoptotic cells is significantly compromised in many chronic inflammatory diseases, including atherosclerosis. Emerging evidence suggests that impairments in efferocytosis drive necrotic core formation and contribute significantly to plaque vulnerability. Recently, it has been appreciated that successive rounds of efferocytosis, termed “continual efferocytosis”, is mechanistically distinct from single efferocytosis and relies heavily on the metabolism and handling of apoptotic cell-derived cargo. In vivo, selective defects in continual efferocytosis drive secondary necrosis, impair inflammation resolution, and worsen atherosclerosis. This Mini Review focuses on our current understanding of the cellular and molecular mechanisms of continual efferocytosis and how dysregulations in this process mediate nonresolving inflammation. We will also discuss possible strategies to enhance efferocytosis when it fails.

Efferocytosis is restricted by axon guidance molecule EphA4 via ERK/Stat6/Mertk signaling following brain injury

“…In addition, ERK1/2 signaling is implicated in promoting actin polymerization and cytoskeletal rearrangement, thereby facilitating the process of efferocytosis [ 32 ]. Importantly, ERK1/2 activation also regulates the production of anti-inflammatory mediators during efferocytosis, promoting the polarization of macrophages toward a pro-resolving phenotype, which contributes to sustained efferocytosis and the resolution of inflammation [ 33 , 34 ]. One crucial transcription factor influenced by ERK1/2 activation to regulate macrophage polarization is Stat6 [ 35 , 36 ].…”

Efferocytosis: An Emerging Therapeutic Strategy for Type 2 Diabetes Mellitus and Diabetes Complications

“… 123 Defective efferocytosis is postulated as a predominantly hazardous player in atherosclerosis, 124 and reinforcement of efferocytosis aids in the reduction of atherosclerosis. 125 , 126 Alternatively, the favorable remediation effect of cardiac function after myocardial infarction (MI) is attributed to cardiac macrophage efferocytosis, which generates VEGF in a CD36-dependent manner to reduce inflammation and promote lymphangiogenesis. 127 The deletion of legumain, a gene encoding endolysosomal cysteine protease that is highly expressed in macrophages, has a prejudicial impact on cardiac function recovery after MI as it causes efferocytosis failure, widespread inflammation, and accumulation of apoptotic cardiomyocytes.…”