RESUMO
[Figure: see text].
Assuntos
Antígenos CD/metabolismo , Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Quimiotaxia de Leucócito , Leucopoese , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/genética , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Células Cultivadas , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Monócitos/imunologia , Receptores de Orexina/metabolismo , Fosforilação , Placa Aterosclerótica , Fator de Transcrição STAT1/metabolismo , Transdução de SinaisRESUMO
Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex nature enabling the detection of multiple motifs named danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers an intracellular signalling cascade mediated through MyD88 or TRIF, leading to the production of pro- and anti-inflammatory cytokines. In this review we explore key novel findings pertaining to TLR signalling in atherosclerosis, including recently described endosomal TLRs and future directions in TLR research.
Assuntos
Aterosclerose/metabolismo , Receptores Toll-Like/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Humanos , Fator 88 de Diferenciação Mieloide/metabolismo , Fatores de Risco , Transdução de SinaisRESUMO
Splenic dendritic cells are crucial for controlling the immune response to malaria by initiating a CD4 gamma interferon (IFN-γ) response early in a blood-stage infection, which contributes to parasite clearance as well as to acute-stage immunopathology. CD8(-) CD11c(high) dendritic cells have been described previously to be important antigen-presenting cells for induction of these CD4 T cell responses in the spleens of Plasmodium chabaudi-infected mice. However, when isolated during the period of maximum parasitemia and shortly thereafter, the dendritic cells transiently lose their ability to stimulate T cells, recovering only as the parasitemia is controlled. This loss of a CD4 T cell response is also observed in vivo during this part of the infection. CD4 T cells from a T cell receptor-transgenic mouse recognizing a peptide of merozoite surface protein 1 (MSP1) injected into BALB/c mice during peak parasitemia proliferate poorly, and very few cells produce IFN-γ and interleukin-2 (IL-2), compared with transgenic T cells injected earlier in the blood-stage infection. CD8(-) dendritic cells at day 10 can process and present peptides on major histocompatibility complex (MHC) class II with an efficiency similar to that of dendritic cells from earlier in infection. The failure of the day 10 dendritic cells to activate MSP1-specific CD4 T cells fully in vitro is associated with reduced expression of CD86 and lower production of IL-12 rather than with induction of inhibitory DC receptors or production of IL-10.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Proteína 1 de Superfície de Merozoito/imunologia , Parasitemia/imunologia , Plasmodium chabaudi/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/patologia , Células Dendríticas/metabolismo , Eritrócitos/parasitologia , Ativação Linfocitária , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/parasitologia , Plasmodium chabaudi/metabolismoRESUMO
Atherosclerosis is intimately coupled to blood flow by the presence of predilection sites. The coupling is through mechanotransduction of endothelial cells and approximately 2000 gene are associated with this process. This paper describes a new platform to study and identify new signalling pathways in endothelial cells covering an atherosclerotic plaque. The identified networks are synthesized in primary cells to study their reaction to flow. This synthetic approach might lead to new insights and drug targets.
Assuntos
Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Biologia Sintética/métodos , Biologia de Sistemas/métodos , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Circulação Sanguínea/genética , Vasos Sanguíneos/fisiologia , Vasos Sanguíneos/fisiopatologia , Simulação por Computador , Células Endoteliais/metabolismo , Genômica , Imageamento Tridimensional , Fatores de Transcrição Kruppel-Like/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/genética , TranscriptomaRESUMO
Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.