Abstract
BackgroundOxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). It has been shown that oxLDL-IC are considerably more efficient than oxLDL in induction of foam cell formation, inflammatory cytokines secretion, and cell survival promotion. Whereas oxLDL is taken up by several scavenger receptors, oxLDL-IC are predominantly internalized through the FCγ receptor I (FCγ RI). This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress.Methodology/FindingsFluorescently labeled lipid and protein moieties of oxLDL co-localized within endosomal and lysosomal compartments in U937 human monocytic cells. In contrast, the lipid moiety of oxLDL-IC was detected in the endosomal compartment, whereas its apolipoprotein moiety advanced to the lysosomal compartment. Cells treated with oxLDL-IC prior to oxLDL demonstrated co-localization of internalized lipid moieties from both oxLDL and oxLDL-IC in the endosomal compartment. This sequential treatment likely inhibited oxLDL lipid moieties from trafficking to the lysosomal compartment. In RAW 264.7 macrophages, oxLDL-IC but not oxLDL induced GFP-tagged heat shock protein 70 (HSP70) and HSP70B', which co-localized with the lipid moiety of oxLDL-IC in the endosomal compartment. This suggests that HSP70 family members might prevent the degradation of the internalized lipid moiety of oxLDL-IC by delaying its advancement to the lysosome. The data also showed that mitochondrial membrane potential was decreased and generation of reactive oxygen and nitrogen species was increased in U937 cell treated with oxLDL compared to oxLDL-IC.Conclusions/SignificanceFindings suggest that lipid and apolipoprotein moieties of oxLDL-IC traffic to separate cellular compartments, and that HSP70/70B' might sequester the lipid moiety of oxLDL-IC in the endosomal compartment. This mechanism could ultimately influence macrophage function and survival. Furthermore, oxLDL-IC might regulate the intracellular trafficking of free oxLDL possibly through the induction of HSP70/70B'.
Highlights
An early event in atherosclerosis is the engorgement of macrophages with lipids
In a recent study we showed that in macrophages, internalized oxLDLIC induces a member of the HSP70 family, heat shock protein 70B’ (HSP70B’), which co-localizes with the lipid moiety of Oxidized low-density lipoproteins (oxLDL)-IC [16]
Investigating the mechanisms controlling the intracellular transport of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC in macrophages is central in understanding foam cell formation, activation, and survival
Summary
An early event in atherosclerosis is the engorgement of macrophages with lipids. It is well established that activated macrophages become lipid-laden foam cells by taking up oxidatively modified low-density lipoprotein (oxLDL), leading to the accumulation of cholesteryl esters (CE) [1]. Circulating oxLDL elicits the production of auto-immune antibodies, predominantly of the proinflammatory IgG1 and IgG3 isotypes, resulting in the formation of oxLDL-containing immune complexes (oxLDL-IC) [2,3,4]. While both oxLDL and oxLDL-IC have been detected in human atherosclerotic plaques [5], oxLDL-IC are considerably more efficient than oxLDL in the induction of foam cell formation [6]. Oxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress
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