RESUMEN
Atherosclerosis contributes to the development of many cardiovascular diseases, which remain the leading cause of death in developed countries. Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. It is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a key factor at all stages of atherosclerosis progression. Cells involved in pathogenesis of atherosclerosis were shown to be activated by soluble factors, cytokines, that strongly influence the disease development. Pro-inflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. In this review, we discuss the latest findings on the role of cytokines in the development and progression of atherosclerosis.
Asunto(s)
Inmunidad Adaptativa , Aterosclerosis/inmunología , Citocinas/inmunología , Inmunidad Innata , Animales , Aterosclerosis/patología , Enfermedad Crónica , HumanosRESUMEN
The pathogenesis of atherosclerosis involves the interplay of haematopoietic, stromal and endothelial cells. Platelet interactions with endothelium and leukocytes are pivotal for atherosclerosis promotion. Glycoprotein (GP) Ibα is the ligand-binding subunit of the platelet GPIb-IX-V receptor complex; its deficiency causes the Bernard-Soulier syndrome (BSS), characterised by absent platelet GPIb-IX-V, macrothrombocytopenia and bleeding. We designed this study to determine the role of platelet GPIbα in the pathogenesis of atherosclerosis using two unique knockout models. Ldlr-/- mice were reconstituted with wild-type (wt), GPIbα-/- (lacks GPIbα) or chimeric IL-4R/GPIbα-Tg (lacks GPIbα extracellular domain) bone marrow and assayed for atherosclerosis development after feeding with pro-atherogenic "western diet". Here, we report that Ldlr-/-mice reconstituted with GPIbα-/- bone marrow developed less atherosclerosis compared to wt controls; accompanied by augmented accumulation of pro-inflammatory CD11b+ and CD11c+ myeloid cells, reduced oxLDL uptake and decreased TNF and IL 12p35 gene expression in the aortas. Flow cytometry and live cell imaging in whole blood-perfused microfluidic chambers revealed reduced platelet-monocyte aggregates in GPIbα-/- mice, which resulted in decreased monocyte activation. Interestingly, Ldlr-/-mice reconstituted with IL-4R/GPIbα-Tg bone marrow, producing less abnormal platelets, showed atherosclerotic lesions similar to wt mice. Platelet interaction with blood monocytes and accumulation of myeloid cells in the aortas were also essentially unaltered. Moreover, only complete GPIbα ablation altered platelet microparticles and CCL5 chemokine production. Thus, atherosclerosis reduction in mice lacking GPIbα may not result from the defective GPIbα-ligand binding, but more likely is a consequence of functional defects of GPIbα-/- platelets and reduced blood platelet counts.
Asunto(s)
Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Síndrome de Bernard-Soulier/metabolismo , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Animales , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Síndrome de Bernard-Soulier/genética , Plaquetas/metabolismo , Trasplante de Médula Ósea , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Quimiocina CCL5/metabolismo , Dieta Occidental , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Subunidad p35 de la Interleucina-12/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/metabolismo , Adhesividad Plaquetaria , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Estructura Terciaria de Proteína , Receptores de Interleucina-4/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We have demonstrated that transcription factors Egr1 and NFAT2 cooperate in regulation of the early stages of T-lymphocyte development, whereas the related factors Egr2 and Egr3 do not cooperate with NFAT2. Egr1 and NFAT2 are shown to cooperatively control gene expression of the regulatory factor Id3 and recombinase Rag2, whose functions are critical for T-lymphocyte differentiation. Thus, the concerted action of the transcription factors Egr1 and NFAT2 can play a crucial role in regulation of the T cell differentiation in vitro due to the cooperative regulation of Id3 and Rag2 gene expression.