RESUMO
This study aimed to investigate atherosclerotic mediators' expression levels in M1 and M2 macrophages and to focus on the influence of diabetes on M1/M2 profiles. Macrophages from 36 atherosclerotic patients (19 diabetics and 17 non-diabetics) were cultured with interleukin-1ß (IL-1ß) or IL-4 to induce M1 or M2 phenotype, respectively. The atherosclerotic mediators' expression was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that M1 and M2 macrophages differentially expressed mediators involved in proteolysis and angiogenesis processes. The proteolytic balance (matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1), MMP-9/plasminogen activator inhibitor-1 (PAI-1) and MMP-9/tissue factor pathway inhibitor-2 (TFPI-2) ratios) was higher in M1 versus M2, whereas M2 macrophages presented higher angiogenesis properties (increased vascular endothelial growth factor/TFPI-2 and tissue factor/TFPI-2 ratios). Moreover, M1 macrophages from diabetics displayed more important proangiogenic and proteolytic activities than non-diabetics. This study reveals that M1 and M2 macrophages could differentially modulate major atherosclerosis-related pathological processes. Moreover, M1 macrophages from diabetics display a deleterious phenotype that could explain the higher plaque vulnerability observed in these subjects.
Assuntos
Aterosclerose/genética , Doenças das Artérias Carótidas/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Macrófagos/metabolismo , Neovascularização Patológica/genética , Idoso , Antígenos de Superfície/genética , Aterosclerose/complicações , Aterosclerose/diagnóstico por imagem , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Angiografia Cerebral , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Fator XIII/genética , Feminino , Regulação da Expressão Gênica , Glicoproteínas/genética , Humanos , Interleucina-10/genética , Interleucina-1beta/genética , Lectinas Tipo C/genética , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/genética , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Receptores de Orexina , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/genética , Estudos Prospectivos , Proteólise , Receptores de Superfície Celular/genética , Receptores de Retorno de Linfócitos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Although neutrophils are crucially involved in inflammation, they have received only little attention in metabolic syndrome (MetS). We hypothesized that neutrophil infiltration into adipose tissue (AT) may occur at an early stage of MetS, in association with modulation of major functions of neutrophils and of their bone marrow production. METHODS: Fifty-six male Sprague-Dawley rats were fed regular (control rats (CRs)) or high-fructose (60%; fructose-fed rats (FFRs)) diets. After 6 weeks, metabolic parameters were measured. Distribution of neutrophils into AT was investigated by immunohistochemistry. Function of circulating neutrophils (activation, reactive oxygen species production, phagocytosis, and apoptosis) was determined by flow cytometry. Granulopoiesis was evaluated by measuring the number and survival characteristics of neutrophil progenitors using bone marrow culture assays and flow cytometry. RESULTS: Compared with the CR group, the FFR group developed MetS (i.e., arterial hypertension, hypertriglyceridemia, fasting hyperglycemia, and greater intra-abdominal AT volume) and presented higher neutrophil infiltration into AT. At resting state, no significant difference for circulating neutrophil functions was observed between the 2 groups. In contrast, circulating neutrophils from the FFR group exhibited higher responses to phorbol-12-myristate-13-acetate for all studied functions, compared with the CR group, suggesting that early MetS induces neutrophil priming. In parallel, a diminished clonal capacity and an increased apoptosis in bone marrow-derived granulocyte progenitors and neutrophil precursors were observed in the FFR group compared with the CR group. CONCLUSIONS: These results provide evidence of an increased infiltration into intra-abdominal AT and modified production, function, and phenotype of neutrophils at an early stage of high-fructose diet-induced MetS.