Low density lipoprotein metabolism by human macrophages activated with low density lipoprotein immune complexes. A possible mechanism of foam cell formation.

Abstract

Human macrophages play a key role in atherogenesis and are believed to be the progenitors of the cholesteryl ester (CE)-laden foam cells present in early atherosclerotic lesions. Several mechanisms by which macrophages accumulate CE have been recently described. One involves a perturbation in LDL metabolism subsequent to macrophage activation. Thus, we decided to study the effect of macrophage activation by immune complexes on N-LDL metabolism. Initially, LDL-containing immune complexes (LDL-IC) were chosen, since increased plasma levels of these IC have been reported in patients with coronary heart disease. Human macrophages stimulated for 22 h with LDL-IC (250 micrograms/ml) and incubated afterwards for 20 h with 10 micrograms/ml 125I-N-LDL showed a six- and fourfold increase in the accumulation and degradation, respectively, of 125I-N-LDL over the values observed in nonstimulated cells. Scatchard analysis of 125I-N-LDL-specific binding suggests an increase (20-fold) in the number of LDL receptors in macrophages stimulated with LDL-IC. We studied other immune complexes varying in size and antigen composition. Some of the IC were able to stimulate, although to a lesser degree, the uptake of N-LDL by macrophages. Lipoprotein IC are more efficient and have the greatest capacity to increase N-LDL uptake and CE accumulation. We conclude that human macrophage activation by LDL-IC leads to an increase in LDL receptor activity and promotes in vitro foam cell formation.

Atherogenesis and the humoral immune response to modified lipoproteins

“…The predominance of IgG over IgM antibodies favors the formation of IgG-containing IC with proinflammatory properties. In vitro studies have demonstrated that immune complexes formed with modified LDL and IgG antibodies have significantly stronger pro-atherogenic (as judged by leading to foam cell formation) and proinflammatory (as judged by the release of proinflammatory cytokines) properties than modified LDL by itself [12,13,56,61]. Clinical studies have shown that high levels of mLDL-IC are related to intima-media thickening and diabetic nephropathy.…”

“…At the same time, the macrophages ingesting isolated LDL-IC become activated and release proinflammatory cytokines, and oxygen active radicals [55]. Insoluble IC prepared with human LDL and rabbit LDL antibody also promote the transformation of macrophages into foam cells [56] and deliver activating signals as a consequence of their interaction with FcγRI [57] resulting in the release of pro-inflammatory cytokines, such as IL-1 and TNF, oxygen active radicals, and metalloproteinases [55,56,58,59]. LDL-IC prepared with human oxLDL and oxLDL antibodies isolated from patients with type 1 diabetes can also induce cholesterol and cholesterol ester accumulation in a variety of macrophage-like cell lines, including THP-1, U937, and MonoMac-6, which are also activated as reflected by the release of pro-inflammatory cytokines, including IL-1., Il-6, IL-12, and TNF [12,13], as well as of metalloproteinases [ MMP-1] [59].…”

Platelets induce monocyte differentiation in serum-free coculture

“…In particular, the formation of foam cells by incubation of MO with lipoproteins has been studied [34]. Furthermore, other lipids like 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the active metabolite of vitamin D 3 , has a profound effect on MO maturation [14,15].…”

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

“…On the other hand, oxLDL is immunogenic and elicits the production of antibodies, predominantly of the proinflammatory IgG1 and IgG3 isotypes (3,4). These antibodies form circulating immune complexes containing oxLDL (oxLDL-IC), and those immune complexes have pro-inflammatory properties (5)(6)(7) and are considerably more efficient than oxLDL in the induction of foam cell formation (8)(9)(10). While the uptake of both oxLDL and oxLDL-IC produce cells morphologically defined as foam cells, there is evidence for distinct molecular differences.…”