Monocyte adhesion and transmigration in atherosclerosis (1994)

One of the earliest cellular events recognized so far in the development of the atherosclerotic lesion is the adherence of monocytes to the endothelium. Adherent monocytes subsequently migrate to the subendothelial space, differentiate to macrophages, accumulate cholesterol esters, and become foam cells. Macrophages are present in all stages of atherogenesis [1]. The normal role of the macrophage is to act as an antigen presenting cell to T lymphocytes, to scavenge and remove noxious materials and to serve as a source of growth regulatory cytokines and molecules. In animal models of atherosclerosis including those of swine and monkey, focal adhesion of monocytes to the endothelium in the lesion-prone regions of large vessels is one of the earliest signs observed [1–9]. Immunohistochemical examination of human arterial specimens has also shown similar monocyte involvement [10–12]. Upon initiation of an inflammatory reaction, specific adhesion molecules on the surface of endothelial cells [13–15] and leukocytes [13,16] mediate the initial loose contact, termed rolling [17–20], and the following tight adhesion of the leukocytes to the luminal surface of the endothelium [13,21]. This is followed by transendothelial migration, during which tight contacts are maintained between the leukocytes and the endothelial cells as observed in vitro [22,23] and in vivo [24,25]. The nature of the molecules and the mechanisms that regulate leukocyte transmigration are poorly understood; more information is available on neutrophil transmigration in vitro [23,26,27]. In addition to monocytes, lymphocytes (but not neutrophils) have been found in the lesions of animal models and in human lesions [28–30]. RANTES, a member of the intercrine cytokine family, has been shown to cause the selective migration of human blood monocytes and T lymphocytes expressing the cell surface antigens CD4 and UCHL1 [31]. Stimulated endothelial cells express mRNA for the neutrophil-activating protein NAP-1/interleukin (IL)-8, which is chemotactic for neutrophils and T lymphocytes [32], but at high concentrations IL-8 is inhibitory for neutrophil adherence [33,34]. This induction could lead to T-lymphocyte migration without neutrophil migration, so that monocyte transmigration in atherosclerotic lesions might precede and direct a subsequent transmigration of lymphocytes. In lesions associated with cardiac transplant rejection, macrophages and T lymphocytes occur in much larger numbers than those seen in hypercholesterolemia-induced atherosclerosis [2,34]. This suggests that a localized immune response may have exacerbated macrophage/T-cell interactions [2]. It has been suggested that only specific subsets of monocytes adhere to the endothelium and enter the intima. Bath and colleagues [35] have demonstrated that monocytes from hypercholesterolemic patients have a markedly higher ability to adhere to cultured endothelial monolayers compared with matched control monocytes. The presence of functionally abnormal monocytes has also been reported in hypercholesterolemic subjects by Stragliotto et al. [36]. In monocytes from these subjects, generation of prostaglandin E2 and 6-keto-prostaglandin F1α in response to n-formyl-methionyl-leucyl-phenyialanine or calcium ionophore A23187 was 1.5 to 3 times higher compared with monocytes from normal controls. These differences were not eliminated when plasma cholesterol levels in the patients were normalized by low-density lipoprotein (LDL) apheresis. In keeping with the abnormalities in the eicosanoid metabolism, monocytes from hypercholesterolemic patients exhibited a defective ability to generate su-peroxide radicals [36]. Furthermore, monocytes from these patients exhibited significantly higher adherence to glass.