Aernoud Fiolet

15 General introduction and thesis outline low-density lipoproteins (“LDL”). 11 On entering the intima, oxidation occurs. The oxidised LDL acts as a danger-associated molecular-pattern for Toll-like receptors of the endothelial cell. 12 In an attempt to avert these undesirable compounds, the immune system is activated in various ways. This is accomplished in the first place by increasing the adhesiveness of the endothelium by an increased expression of “vascular cell adhesion molecule – 1” (VCAM-1)ontheintimalsideof theendothelialcell,whichisregulatedbycytokines. 13 Such upregulated expression is seen within a week of initiating an atherogenic diet in an experimental setting. 14 This adhesion molecule will most importantly interact with the “very late activation antigen 4”, a so-called integrin. These integrins can be foundontheoutersideofmonocytes rollingdowntheendotheliumandareactivated by chemokines expressed by the endothelium. The most important chemokine responsible for the attraction of these monocytes is “monocyte chemoattractant protein 1”. This specific chemokine is mainly expressed in response to oxidised LDL in the intima and not so much by native LDL. 15,16 The receptor for monocyte chemoattractant protein 1 is CCR2. 17 The importance of this receptor and the link between the oxidised LDL and monocyte attraction via the monocyte attractant protein 1 is evidenced by the upregulation of CCR in hypercholesterolaemia. This upregulation increases the sensitivity of the “monocyte-to-monocyte attractant protein 1”. 18 This chemokine is localised in the subendothelial space and leads the monocyte from the endothelial surface into the intima. 19 Thus, by increasing the expression of adhesion molecules on the endothelium and by activating the integrins on the monocyte, the rolling monocyte is halted and firm adhesion to the endothelium occurs, after which chemokines introduce the monocyte into the intima. 20 Monocytes, which become macrophages under the influence of “monocyte-colony stimulating factor” produced by endothelial cells and bone marrow, have multiple purposes. 21,22 They serve as scavenger cells, antigen-presenting cells, and secretory cells, with an extremely diverse spectrum of secretion. Conventionally, after scavenging the injured site, macrophages migrate from the injury. During a longer stay in a lesion, the macrophage differentiates into specific phenotypes. The M1 phenotype macrophage is stimulated by pro-inflammatory cytokines and oxidised LDL and expresses multiple pro-inflammatory cytokines itself, maintaining the pro-inflammatory state. Its effect are counterbalanced by M2 macrophages, which have anti-inflammatory effects. 23 M1 macrophages are dominant in the shoulder regions of the growing plaque, while M2 macrophages are found in the