Induction of the unfolded protein response after monocyte to macrophage differentiation augments cell survival in early atherosclerotic lesions

Abstract

Endoplasmic reticulum (ER) stress causes macrophage cell death within advanced atherosclerotic lesions, thereby contributing to necrotic core formation and increasing the risk of atherothrombotic disease. However, unlike in advanced lesions, the appearance of dead/apoptotic macrophages in early lesions is less prominent. Given that activation of the unfolded protein response (UPR) is detected in early lesion-resident macrophages and can enhance cell survival against ER stress, we investigated whether UPR activation occurs after monocyte to macrophage differentiation and confers a cytoprotective advantage to the macrophage. Human peripheral blood monocytes were treated with monocyte colony-stimulating factor to induce macrophage differentiation, as assessed by changes in ultrastructure and scavenger receptor expression. UPR markers, including GRP78, GRP94, and spliced XBP-1, were induced after macrophage differentiation and occurred after a significant increase in de novo protein synthesis. UPR activation after differentiation reduced macrophage cell death by ER stress-inducing agents. Further, GRP78 overexpression in macrophages was sufficient to reduce ER stress-induced cell death. Consistent with these in vitro findings, UPR activation was observed in viable lesion-resident macrophages from human carotid arteries and from the aortas of apoE(-/-) mice. However, no evidence of apoptosis was observed in early lesion-resident macrophages from the aortas of apoE(-/-) mice. Thus, our findings that UPR activation occurs during macrophage differentiation and is cytoprotective against ER stress-inducing agents suggest an important cellular mechanism for macrophage survival within early atherosclerotic lesions.

Molecular Biology of Atherosclerosis

“…Despite the dire consequences of intense or prolonged UPR, limited ER stress in early lesions, with adaptive increases in BiP, actually enhanced macrophage survival (422). Other examples of a need for balanced, modest activation have been reported, as in the limited oxidative stress required to activate Nrf2.…”

Protein Misfolding and Endoplasmic Reticulum Stress in Chronic Lung Disease

“…The UPR can also stimulate programs aimed at increas ing the surface area and volume of the ER, enhancing the cellular capacity for folding and processing 12 and it has been shown to have a key role in cellular differ entiation processes. 13 If these initiatives do not restore cellular homeostasis, the UPR can ultimately promote cell death. Thus, it is not surprising that persistent deregulation of the UPR can contribute to a wide range of diseases, including various neurodegenerative, cardiovascular, and metabolic diseases.…”

Endoplasmic Reticulum Stress Controls M2 Macrophage Differentiation and Foam Cell Formation

“…Unfolded protein response (UPR) is an adaptive intra-cellular signaling pathway that responds to ER stress by attenuating global protein translation and degrading unfolded proteins. During monocyte differentiation by macrophage colony stimulating factor (M-CSF), the ER undergoes structural as well as functional reorganization to perform the new cell functions, leading to ER stress and up-regulated UPR (11)(12)(13)(14). In mouse models of diet-induced insulin resistance and atherosclerosis, up-regulated UPR markers are detected in intimal macrophages at early stages of vascular inflammation, even before the formation of fatty streaks or atherosclerotic plaques (15), and as the plaque evolves into late stages, adverse environmental changes, including increased macrophage-free cholesterol, accelerate macrophage apoptosis through an ER stress-dependent mechanism (16).…”