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. (Circ J 2016; 80: 2259-2268).

Figure 1

Role of fatty-acid-binding protein 4 (FABP4) in endoplasmic reticulum (ER) stress-induced apoptosis in atherosclerosis. FABP4, also known as adipocyte protein 2, induces ER stress via LXR-SCD1-mediated de novo lipogenesis. Inhibition of FABP4 and the macrophage lipid chaperone targeting-FABP4 attenuate ER stress-induced apoptosis. Two apoptotic pathways are involved in the action of the ER stress response, including mitochondria-dependent apoptosis and mitochondria-independent apoptosis.

Figure 2

Schematic model of JNK- and IKKα-mediated regulation of Akt signaling in macrophages. Note the red errors indicating JNK1-mediated suppression and IKKα related activation of Akt signaling. ER, endoplasmic reticulum; IKK, IκB kinase; JNK, c-Jun NH₂-terminal kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog.

Figure 3

Apoptosis pathways regulated by Akt signaling.

Figure 4

Physiological macrophage efferocytosis in atherosclerotic lesions involves a number of efferocytotic receptors, bridging molecules, and apoptotic cell ligands. The efferocytosis receptor complexes that affect atherosclerosis development in mice include SR-BI, TG2-αvβ3, MERTK-αvβ5, and LRP1-CRT-ABCA7. SR-BI interaction with apoptotic cell phosphatidylserine (PS) stimulates Src membrane recruitment and phosphorylation, leading to downstream activation of phosphoinositide 3-kinase and Rac1 to promote formation of the phagocytic cup and efficient efferocytosis. Efferocytosis by SR-BI and the other receptors stimulates anti-inflammatory signaling and promotes phagocyte survival. In advanced atherosclerotic lesions, enhanced oxidative stress and inflammation leads to defective efferocytosis, resulting in secondary necrotic death, heightened inflammation, and cytotoxicity.