Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis

Abstract

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...

Dynamic T cell–APC interactions sustain chronic inflammation in atherosclerosis

“…On the other hand, DC subsets, including CD11c + CD11b -and CD11b + CD11c + cells, may be pivotal for T cell activation and inflammation during atherosclerosis, similar to their well-defined role in immune responses. Depletion of DCs has also been shown to elevate circulating LDL cholesterol (71). Thus, the observed reduction of lesion size after depletion of APCs in Cd11c-DTR + mice in our study may represent the sum total of all these effects.…”

The functional role of dendritic cells in atherogenesis (Review)

“…on the other hand, Gautier et al (44) found that the expansion of the dc population was not associated with an acceleration of aTS plaque progression in either ldl receptor-deficient or apoE-deficient mice. In these experimental situations, the expansion of the dc population was associated with an atheroprotective decrease in plasma cholesterol levels.…”

“…The novel in vivo evidence that dcs broadly impact the circulating levels of cholesterol and immune responses in aTS opens new therapeutic horizons in the treatment of aTS (44).…”

Dendritic Cells and Regulatory T Cells in Atherosclerosis

“…Increases in DC populations induced by the overexpression of human Bcl-2 were found to enhance T cell activation and to increase plasma concentrations of Th1-driven IgG2c autoantibodies directed against oxidation specific epitopes, but to decrease plasma cholesterol concentrations (Gautier et al, 2009). …”