**1. Introduction**

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54 Current Trends in Atherogenesis

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Atherosclerosis has been formerly considered as a lipid-mediated disease. It has long been assumed that atherogenesis could be simply explained by lipid accumulation in the vessel wall leading to endothelial dysfunction with adverse vascular wall remodelling. However, over the last decade, a number of studies have clearly demonstrated that lipids are not the whole story in the pathogenesis of atherosclerosis. Accumulating evidence has shown that inflammation and the immune system play a major role in the initiation, progression and destabilization of atheromata [1,2,3,4]. Mainly innate immunity pathways have long been believed to contribute to atherogenesis, and special attention has been given to macrophag‐ es, because these effector cells are important for intracellular lipid accumulation and foam cell formation [5]. Yet, although macrophages constitute the largest cell population, other immune cell subsets, namely dendritic cells (DCs) and T cells, can also be found within athe‐ rosclerotic plaques and seem to participate in immune responses during atherogenesis.

DCs are the pacemakers of the immune system. These professional antigen-presenting cells play a key role in inducing adaptive immune responses on the one hand, and are critically involved in promoting and maintaining immune tolerance on the other [6]. They originate from hematopoietic stem cells in the bone marrow and circulate as precursors in the blood stream, taking residence in target tissues at sites of potential antigen entry. Within blood vessels [7] and other tissues, they give rise to immature interstitial DCs that act as sentinels, which continuously and efficiently sample the antigenic content of their microenvironment. In the steady state, immature DCs capture harmless self-antigens in the absence of inflam‐ matory signals. They might enter the regional lymph nodes to present the self-antigen to na‐ ïve or resting T cells, which will be deleted by apoptosis, silenced by the induction of anergy

© 2013 Van Brussel et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

or primed to become regulatory T cells [8]. In contrast, when infection and tissue damage occur, immature DCs take up antigens in the presence of inflammatory signals, which evokes activation and functional transformation into mature DCs. Meanwhile, they exit the non-lymphoid tissues to migrate via afferent lymph vessels to lymphoid tissues, where they completely mature. Mature DCs present short peptide fragments, which are bound to the surface molecules CD1 or major histocompatibility complex (MHC)-I or MHC-II. Conse‐ quently, they activate (naïve) T and B lymphocytes that recognize the presented antigen [9]. Morphological changes occur as well during the DC life cycle: DC precursors are often small, round-shaped cells that turn into larger cells with an irregular (star-like) shape and cytoplasmic protrusions (dendrites) as the cell matures, while migrating DCs are also called veiled cells, as they possess large cytoplasmic 'veils' rather than dendrites [10].

Following the first observation of DCs in human arteries in 1995 [11], numerous studies sug‐ gest that these cells presumably play a crucial role in directing innate or adaptive immunity against altered self-antigens present in atherosclerosis. Localization of DCs nearby vasa vasorum allows monitoring of the major access pathways to the vessel wall and screening of the tissue environment for the appearance of exogenous and endogenous stressors [12]. Once sufficiently activated, DCs in the arterial wall might present the (modified auto-) anti‐ gens, such as oxidized epitopes on apoptotic cells, oxidized low density lipoproteins (oxLDL) or heat shock proteins (Hsp) to T cells and initiate inflammatory responses.

**Figure 1.** *Effects of oxLDL on monocyte differentiation.* Expression of CD14, CCR-6 and CD1a after 24h incubation of monocytes with 10 µg/mL oxLDL or 50 µg/mL oxLDL points to differentiation to a phenotype with characteristics of

Dendritic Cells in Atherogenesis: From Immune Shapers to Therapeutic Targets

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Apart from the induction of monocyte differentiation into DCs, oxLDL can also activate DCs, as demonstrated by several *in vitro* studies. After 24h incubation with high concentra‐ tions of oxLDL (50 µg/mL), expression of activation markers CD40, CD80 and CD83 was sig‐ nificantly upregulated (figure 2), and endocytotic capacity was significantly reduced (figure

**Figure 2.** *Effects of oxLDL on maturation of monocyte-derived DCs.* Expression of maturation markers CD40, CD80 and CD83 after 24h incubation of immature monocyte-derived DCs with 10 µg/mL or 50 µg/mL oxLDL (N=4). Black bars represent the positive control for DC maturation, monocyte-derived DCs stimulated with lipopolysaccharide (LPS; 0.1 µg/mL). \*\*\*P<0.001, \*\*P<0.01, \*P<0.05 versus control, Repeated Measures ANOVA and Dunnett's post-hoc test.

DCs (N=3). \*\*\*P<0.001, \*P<0.05 versus control, Repeated Measures ANOVA and Dunnett's post-hoc test.

3; own unpublished data).
