Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis

Abstract

Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes. Akt displays isoform-specific effects on atherogenesis, which vary with different vascular cell types. Loss of macrophage Akt2 promotes the anti-inflammatory M2 phenotype and reduces atherosclerosis. However, Akt isoforms are redundant with regard to apoptosis. c-Jun NH2-terminal kinase (JNK) is a pro-apoptotic effector of the UPR, and the JNK1 isoform opposes anti-apoptotic Akt signaling. Loss of JNK1 in hematopoietic cells protects macrophages from apoptosis and accelerates early atherosclerosis. IκB kinase α (IKKα, a member of the serine/threonine protein kinase family) plays an important role in mTORC2-mediated Akt signaling in macrophages, and IKKα deficiency reduces macrophage survival and suppresses early atherosclerosis. Efferocytosis involves the interaction of receptors, bridging molecules, and apoptotic cell ligands. Scavenger receptor class B type I is a critical mediator of macrophage efferocytosis via the Src/PI3K/Rac1 pathway in atherosclerosis. Agonists that resolve inflammation offer promising therapeutic potential to promote efferocytosis and prevent atherosclerotic clinical events.

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

“…The death receptor Fas and downstream signaling are known as a representative extrinsic pathway of apoptosis in macrophages . In contrast, Akt signaling, which is constitutively active in macrophages, is known to be a major anti‐apoptotic pathway in macrophages . The present study showed that Fas‐mediated signaling and the PI3K/Akt pathway play a role in the apoptosis of hepatic macrophages, and that CHI3L1 promotes the apoptosis of hepatic macrophages by decreasing Fas expression and activating Akt signaling.…”

Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages

“…As plaques progress, efferocytosis becomes defective, which promotes the formation of clinically dangerous necrotic plaques (Thorp and Tabas, 2009; Linton et al, 2016). To study the consequences of defective macrophage mitochondrial fission in this setting, Drp1 f/fl Lysmcre +/ − (Cre−/−) and Drp1 f/fl Lysmcre +/ − (Cre+/−) mice were crossed onto the Ldlr − / − background and fed a high-fat Western-type diet (WD) for 12 weeks to induce advanced atherosclerosis.…”

“…i.e. , plaque necrosis and induced inflammation, are critical in promoting plaque disruption and acute vascular thrombosis (Schrijvers et al, 2005; Thorp and Tabas, 2009; Linton et al, 2016). Impaired efferocytosis in advanced lesions almost certainly has multiple etiologies.…”

Monocyte-Macrophages and T Cells in Atherosclerosis

“…A lesional macrophage resolution process that has received particular attention in the field of atherosclerosis is efferocytosis (Tabas, 2005; Schrijvers et al, 2007; Linton et al, 2016; Van Vre et al, 2012). Efferocytosis is mediated through phagocyte receptors, apoptotic cell ligands, bridging proteins, and chemoattractants.…”