Abstract
Polymorphisms in the apolipoprotein E (apoE) gene are risk factors for chronic inflammatory diseases including atherosclerosis. The gene product apoE is synthesized in many cell types and has both lipid transport–dependent and lipid transport–independent functions. Previous studies have shown that apoE expression in myeloid cells protects against atherogenesis in hypercholesterolemic ApoE−/− mice. However, the mechanism of this protection is still unclear. Using human APOE gene replacement mice as models, this study showed that apoE2 and apoE4 expressed endogenously in myeloid cells enhanced the inflammatory response via mechanisms independent of plasma lipoprotein transport. The data revealed that apoE2-expressing myeloid cells contained higher intracellular cholesterol levels because of impaired efflux, causing increasing inflammasome activation and myelopoiesis. In contrast, intracellular cholesterol levels were not elevated in apoE4-expressing myeloid cells, and its proinflammatory property was found to be independent of inflammasome signaling and related to enhanced oxidative stress. When ApoE−/− mice were reconstituted with bone marrow from various human APOE gene replacement mice, effective reduction of atherosclerosis was observed with marrow cells obtained from APOE3 but not APOE2 and APOE4 gene replacement mice. Taken together, these results documented that apoE2 and apoE4 expression in myeloid cells promotes inflammation via distinct mechanisms and promotes atherosclerosis in a plasma lipoprotein transport–independent manner.
Highlights
The APOE gene encoding the apolipoprotein E protein is one of the most widely studied genes in biomedical research [1]
Enhanced interleukin (IL)-6 production was observed from leukocytes of APOE2 and APOE4 gene replacement mice similar to that observed with blood from ApoE−/− mice (Fig. 1A)
We found that oxidized LDL (oxLDL) incubation resulted in higher hydrogen peroxide levels in APOE4 macrophages than APOE2 and APOE3 macrophages (Fig. 7D)
Summary
The APOE gene encoding the apolipoprotein E (apoE) protein is one of the most widely studied genes in biomedical research [1]. ApoE is synthesized in many cell types including hepatocytes, adipocytes, macrophages, smooth muscle cells, and in the brain [24,25,26] It has multiple functions both intracellularly and extracellularly in mediating lipid transport and cell homeostasis [24,25,26]. The interaction between extracellular apoE and specific cell surface receptors in the LDL receptor–related protein family regulates cell signaling events in various cell types, including the activation of endothelial nitric oxide synthase in endothelial cells [29, 30], inhibition of vascular smooth muscle cell proliferation and migration [31], and suppression of toll-like receptor activation by increasing macrophage polarization toward the anti-inflammatory M2 phenotype [32]. Unique apoE isoform properties in myeloid cell inflammation underlying the increased risk of both cardiovascular and neurodegenerative diseases in ε4 carriers [36]. The objective of this study is to delineate the mechanism by which different apoE isoforms expressed in myeloid cells influence inflammation and the consequential effect on atherosclerosis
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