‘Danger’ effect of low-density lipoprotein (LDL) and oxidized LDL on human immature dendritic cells

Abstract

SummaryDendritic cell (DC) maturation may accelerate autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and may contribute to accelerated atherosclerosis seen in these patients. The immune system responds to both exogenous and endogenous 'dangerous' signals that can induce dendritic cell maturation. We have found that autologous plasma contains danger signals that induce up-regulation of major histocompatibility complex (MHC) class II and co-stimulatory molecules in immature DCs (iDCs). The objective of this study was to determine whether low-density lipoprotein (LDL) and/or oxidized LDL (oxLDL) constitute danger signals, and to assess the effect of exposure to LDL and oxLDL following monocyte differentiation into iDCs in lipoprotein-deficient serum (LPDS). IDCs were generated in the presence of autologous plasma or LPDS. Expression of maturation and migration molecules was evaluated using flow cytometry, and morphology was assessed by light microscopy. Pro-or anti-apoptotic effect was determined using annexin V and propidium iodide binding. Phagocytosis of apoptotic cells was evaluated using autologous plasma or LPDS. LDL and oxLDL were clearly able to slightly up-regulate levels of HLA-DR and co-stimulatory molecule CD86. High oxLDL concentrations (50-100 mg/ml) were associated with expression of additional maturation molecules. Moreover, iDCs that were prepared in LPDS showed partial maturation following exposure to LDL and oxLDL, and improved tolerogenic apoptotic cell uptake. This study suggests that oxLDL, and to some extent LDL, are at least partly responsible for the iDC 'danger' response induced by autologous plasma.

CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice

“…Since ApoE is expressed at appreciable levels in the skin, it can be speculated that its absence can lead to the accumulation of lipids, which would otherwise be exported to the liver by ApoE through the process of reverse cholesterol transport. It has been demonstrated that hyperlipidemia can affect DC maturation while retaining DC antigen processing and presentation capacity to prime T cells (39)(40)(41). Indeed, the expression of CD86 is increased in dermal DCs of hCD1Tg HJ1Tg Apoe -/-mice.…”

“…It has been demonstrated that hyperlipidemia can change DC maturation and thus function (39)(40)(41). To test the possibility that alterations in DC function can lead to the heightened production of IL-17A by HJ1 T cells, we isolated DCs from the LNs of hCD1Tg, hCD1Tg Apoe -/-, and Apoe -/-mice and incubated them with either normal mouse serum from C57BL/6 mice or hyperlipidemic serum from Apoe -/-mice.…”

Dendritic cells and their role in atherogenesis

“…101 In the arterial intima, immature DCs can be activated by various stimuli. [101][102][103][104][105][106] Cellular components, released from dying cells, collectively called damage-associated molecular patterns and pathogen-associated molecular patterns that originate from microbes and viruses can induce the activation and maturation of DCs. [7][8][9] Ultrastructural analysis of the nondiseased intima of athero-prone areas of the aorta has shown that in this location, there is a casual presence of dying cells and cells exhibiting signs of destruction.…”

Cardiac Allograft Vasculopathy

“…Furthermore, LDL and oxidized LDL are able to upregulate levels of HLA-DR and the costimulatory molecule CD86 in immature DCs. 27 Moreover, lipids may sequester activated DCs 28 in the allograft, where they aggravate local immune responses. Thus, alloantigen-independent factors might indirectly or directly trigger alloimmune responses by inducing endothelial dysfunction, activating complement and coagulation pathways, recruiting inflammatory cells, promoting trafficking of DCs into the allograft, and regulating T-cell differentiation (Figure).…”