Background-Because apoptotic cell clearance appears to be defective in advanced compared with early atherosclerotic plaques, macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. Methods and Results-We first evaluated the impact of targeted protection of macrophages against apoptosis at both early and advanced stages of atherosclerosis. Increased resistance of macrophages to apoptosis in early atherosclerotic lesions was associated with increased plaque burden; in contrast, it afforded protection against progression to advanced lesions. Conversely, sustained induction of apoptosis in lesional macrophages of advanced lesions resulted in a significant increase in lesion size. Such enhanced lesion size occurred as a result not only of apoptotic cell accumulation but also of elevated chemokine expression and subsequent intimal recruitment of circulating monocytes. Conclusions-Considered together, our data suggest that macrophage apoptosis is atheroprotective in fatty streak lesions, but in contrast, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, leading to enhanced atherogenesis. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ inflammation Ⅲ leukocytes Ⅲ macrophages Ⅲ pathology Ⅲ survival A therosclerosis is an inflammatory vascular disease characterized by the intimal accumulation of macrophage foam cells, cell death, and chronic arterial inflammation. 1 Macrophage apoptosis has been identified as a prominent feature of atherosclerotic plaques because macrophage cell death is believed to support necrotic core growth. The apoptotic process is controlled by intracellular levels of proapoptotic and antiapoptotic proteins such as those of the Bcl-2 family. Indeed, the relative expression of proapoptotic (eg, Bax and Bak) and antiapoptotic proteins (eg, Bcl-2 and Bcl-xL) of the Bcl-2 family determines the overall sensitivity of the cell to apoptotic stimuli. In macrophages of atherosclerotic lesions, the proapoptotic Bax and Bak proteins predominate, whereas the antiapoptotic Bcl-2 and Bcl-xL are deficient, 2,3 thereby arguing for their enhanced susceptibility to apoptosis. However, the impact of macrophage apoptosis on plaque progression remains to be specifically investigated. Clinical Perspective p 1804Recent studies have shed light on the potential impact of apoptosis on atherosclerotic lesion progression. Indeed, disruption of either the proapoptotic molecule Bax in bone marrow-derived cells 4 or the antiapoptotic factor AIM 5 has revealed that apoptosis attenuates early plaque formation.However, because apoptotic cells accumulate preferentially in advanced rather than in early lesions, 6,7 macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. 8 In addition, apoptotic cell clearance appears to be defective in advanced lesions but efficient in early ones. 9 Moreover, apoptotic cells may possess proinflammatory properties, in part as a result of t...

Background-Immunoinflammatory mechanisms are implicated in the atherogenic process. The polarization of the immune response and the nature of the immune cells involved, however, are major determinants of the net effect, which may be either proatherogenic or antiatherogenic. Dendritic cells (DCs) are central to the regulation of immunity, the polarization of the immune response, and the induction of tolerance to antigens. The potential role of DCs in atherosclerosis, however, remains to be defined. Methods and Results-We created a mouse model in which the lifespan and immunogenicity of conventional DCs are enhanced by specific overexpression of the antiapoptotic gene hBcl-2 under the control of the CD11c promoter. When studied in either low-density lipoprotein receptor-deficient or apolipoprotein E-deficient backgrounds, DC-hBcl2 mice exhibited an expanded DC population associated with enhanced T-cell activation, a T-helper 1 and T-helper 17 cytokine expression profile, and elevated production of T-helper 1-driven IgG2c autoantibodies directed against oxidationspecific epitopes. This proatherogenic signature, however, was not associated with acceleration of atherosclerotic plaque progression, because expansion of the DC population was unexpectedly associated with an atheroprotective decrease in plasma cholesterol levels. Conversely, depletion of DCs in hyperlipidemic CD11c-diphtheria toxin receptor/ apolipoprotein E-deficient transgenic mice resulted in enhanced cholesterolemia, thereby arguing for a close relationship between the DC population and plasma cholesterol levels. Conclusions-Considered together, the present data reveal that conventional DCs are central to the atherosclerotic process, because they are directly implicated in both cholesterol homeostasis and the immune response. Key Words: atherosclerosis Ⅲ immune system Ⅲ homeostasis Ⅲ dendritic cells Ⅲ lymphocytes D endritic cells (DCs) are the most potent antigen-presenting cells. Indeed, DCs possess a markedly elevated capacity to stimulate T cells, B cells, and natural killer T cells and to drive T-cell differentiation along both T-helper 1 (Th1) and T-helper 2 (Th2) pathways. 1 Moreover, DCs are known to favor tolerance to antigens, possibly via the generation of regulatory T cells. 2 As major regulators of immune responses and T-cell polarization, DCs are potentially key players in chronic inflammatory diseases such as atherosclerosis. Indeed, available evidence suggests that immune responses are directly implicated in the pathogenesis of atherosclerosis. 3,4 Although the presence of DCs has been reported in atherosclerotic plaques, 5-7 no mechanistic insight into the potential central immunoregulatory role of DCs in the immunoinflammatory dimension of atherosclerosis has been provided in atherosclerosis-prone mice. Modulation of the capacity of DCs to induce an immune response may facilitate evaluation of their impact on the pathogenesis of atherosclerosis. Indeed, enhancement of the lifespan of DCs has been reported to increase their immunogen...