Efferocytosis in atherosclerotic lesions: Malfunctioning regulatory pathways and control mechanisms

Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

“…A generally accepted definition of efferocytosis is the clearance of apoptotic cells (ACs) by professional or nonprofessional phagocytic cells [13][14][15][16]. A large and ever-growing body of literature has demonstrated that the most important steps in the formation of atherosclerotic plaques are the accumulation of inflammatory cells (viz.…”

“…Most importantly, defective efferocytosis of inflammatory apoptotic macrophages and macrophage foam cells results in their secondary necrosis and thereby contributes to the formation of an enlarged necrotic core, which weakens the plaque and makes it susceptible to rupture [19]. On the other hand, several studies have indicated that efficient removal of ACs by efferocytosis plays a protective role in atherogenesis by inhibiting the formation and progression of plaques, by preventing necrosis of plaques, and by reducing the inflammatory component inherent of atherosclerotic plaques [13,14].…”

“…Thus, a macrophage can clear several ACs rather than only a single AC, revealing the capacity of macrophages for continued clearance of ACs [14]. Efferocytosis includes several steps: the production of "Find-Me" signals such as lysophosphatidylcholine (LysoPC), Fractalkine (CX3CL1), and sphingosine-1-phosphate (S1P); the production of "Eat-Me" signals such as phosphatidylserine (PtdSer), milk fat globule-EGF factor 8 (MFG-E8), Mer tyrosine kinase (MerTK), Growth arrest-specific 6 (Gas6), and Protein S; engulfment such as ATP-binding cassette transporter A7 (ABCA7), interferon regulatory factor (IRF) 5 and 8, and peroxisome proliferator-activated receptor delta/gamma (PPAR)-δ/γ; and eventually secretion of anti-inflammatory cytokines (as post-engulfment) [13,14] (Table 1). For efferocytosis to work effectively, the many steps need to be performed in correct order.…”

Efferocytosis: molecular mechanisms and pathophysiological perspectives

“…32 A defect in different efferocytosis mediators leads to the accumulation of apoptotic cells inside the plaques and to the acceleration of atherosclerotic disease. 32 For example, a study showed that Gas6 deficiency contributed to atherosclerosis development by reducing phagocyte recruitment in the lesions 33 while a defect in Mer function impaired the clearance of apoptotic cells promoting atherosclerosis progression. 34 Hence, because of the key role of macrophages in the pathogenesis of atherosclerosis, the detailed knowledge of mechanisms of efferocytosis mediated by this cells can open promising windows for treating atherosclerotic disease.…”

“…Therefore, macrophages and efferocytosis process play a very important role in developing atherosclerosis . A defect in different efferocytosis mediators leads to the accumulation of apoptotic cells inside the plaques and to the acceleration of atherosclerotic disease .…”