RESUMEN
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.
Asunto(s)
Apoptosis/inmunología , Arteritis/inmunología , Arteritis/patología , Aterosclerosis/inmunología , Aterosclerosis/patología , Macrófagos/patología , Animales , Apolipoproteínas E/genética , Arterias/inmunología , Arterias/patología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Caspasa 3/metabolismo , Epítopos/inmunología , Epítopos/metabolismo , Genes bcl-2/genética , Humanos , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxidación-Reducción , Fosfolípidos/inmunología , Fosfolípidos/metabolismo , Transgenes/fisiologíaRESUMEN
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 oxidation-specific 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.
Asunto(s)
Aterosclerosis/etiología , Colesterol/sangre , Células Dendríticas/inmunología , Inmunidad , Animales , Autoanticuerpos , Proliferación Celular , Citocinas , Células Dendríticas/citología , Genes bcl-2/genética , Homeostasis , Activación de Linfocitos , Ratones , Ratones Transgénicos , Modelos AnimalesRESUMEN
Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BI gene inactivation of the hypomorphic SR-BI allele in hepatocytes (hypomSR-BI-KO(liver)) was associated with high plasma TC concentrations, increased plasma free cholesterol/TC (FC/TC) ratio, and a lipoprotein-cholesterol profile typical of SR-BI-/- mice. Plasma TC levels were increased 2-fold in hypomSR-BI and control mice fed an atherogenic diet, whereas hypomSR-BI-KO(liver) and SR-BI-/- mice developed severe hypercholesterolemia due to accumulation of FC-rich, VLDL-sized particles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold) compared with that in controls, but to a much lower degree than in hypomSR-BI-KO(liver) (32-fold) and SR-BI-/- (48-fold) mice. The latter models did not differ in either plasma lipid levels or in the capacity of VLDL-sized lipoproteins to induce macrophage cholesterol loading. However, reduced atherosclerosis in hypomSR-BI-KO(liver) mice was associated with decreased lesional macrophage content as compared with that in SR-BI-/- mice. These data imply that, in addition to its major atheroprotective role in liver, SR-BI may exert an antiatherogenic role in extrahepatic tissues.
Asunto(s)
Aterosclerosis/genética , Hígado/metabolismo , Receptores Depuradores de Clase B/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Alelos , Animales , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Apolipoproteínas/sangre , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Dieta Aterogénica , Femenino , Expresión Génica/genética , Interleucina-6/sangre , Lipoproteínas/sangre , Lipoproteínas/química , Lipoproteínas/genética , Hígado/patología , Macrófagos/química , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores Depuradores de Clase B/deficiencia , Receptores Depuradores de Clase B/metabolismo , Factores Sexuales , Triglicéridos/sangreRESUMEN
OBJECTIVE: Premature atherosclerosis is a characteristic feature of systemic lupus erythematosus, a prototypic autoimmune disease. The principle cellular and molecular mechanisms which underlie such accelerated atherosclerosis are indeterminate. METHODS AND RESULTS: The pathophysiology of lupus-mediated atherogenesis was evaluated in a novel animal model involving transplantation of bone marrow cells from the lupus prone strain gld into Ldl-r(-/-) mice. Diet-induced atherogenesis in lethally-irradiated Ldl-r(-/-) mice transplanted with gld bone marrow cells resulted in accelerated atherosclerosis (+65%) as compared with control mice transplanted with wild-type marrow cells. Enhanced atherogenesis was associated with enhanced activation of both B and T lymphocytes and with arterial inflammation involving endothelial cell activation, monocyte recruitment, and accumulation of apoptotic debris, macrophages, and CD4 T cells, but was independent of plasma lipid levels and renal function. CONCLUSIONS: Our data support the contention that despite the absence of both disturbed cholesterol homeostasis and renal dysfunction in autoimmune gld-->Ldl-r(-/-) mice, lupus disease induces enhanced activation of the immune system and acts locally on the vasculature to induce inflammation, together with accumulation of apoptotic debris, macrophages, and CD4 T cells, thereby accelerating plaque progression.
Asunto(s)
Aterosclerosis/inmunología , Aterosclerosis/fisiopatología , Citocinas/metabolismo , Lupus Eritematoso Sistémico/inmunología , Animales , Anticuerpos Antifosfolípidos/sangre , Apoptosis/inmunología , Apoptosis/fisiología , Trasplante de Médula Ósea , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Sistema Inmunológico/fisiología , Metabolismo de los Lípidos , Lipoproteínas/metabolismo , Lupus Eritematoso Sistémico/fisiopatología , Macrófagos/citología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Probabilidad , Quimera por Radiación , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
Impaired immune function and associated immunosuppression are hallmarks of septic syndromes. As part of an overall deactivation of the immune system, profound depletion of dendritic cells (DCs) occurs in both septic patients and septic mice. Such depletion of DCs is potentially associated with immunosuppression and with failure to induce a protective Th1 immune response; it may equally be predictive of fatal outcome in septic patients. To evaluate the impact of enhanced DC survival on LPS-induced immunosuppression and on survival after LPS-induced septic shock, we created a transgenic mouse model specifically overexpressing the human form of the antiapoptotic protein Bcl-2 in DCs (DC-hBcl-2 mice). DCs derived from DC-hBcl-2 mice exhibited higher resistance to maturation-induced apoptosis after LPS treatment both in vitro and in vivo. Moreover, prolongation of DC survival diminished sublethal LPS-induced DC loss and immunosuppression, with maintenance of the differentiation potential of Th1 cells and enhanced T cell activation. Such modulation of the immune response appears to constitute a key feature of the attenuated mortality observed after LPS-induced shock in DC-hBcl-2 mice. Our study therefore identifies DC death as a key determinant of endotoxin-induced immunosuppression and mortality in mice.