RESUMO
AIMS/HYPOTHESIS: Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. METHODS: We generated a model of the metabolic syndrome by backcrossing KKAy ( + ) with Apoe ( -/- ) mice (KKAy ( + ) Apoe ( -/- )) and studied the role of CCR2 in this model system. RESULTS: KKAy ( + ) Apoe ( -/- ) mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy (+) Apoe ( -/- ) mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. CONCLUSIONS/INTERPRETATION: CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome.
Assuntos
Apolipoproteínas E/metabolismo , Síndrome Metabólica/metabolismo , Receptores CCR2/metabolismo , Animais , Apolipoproteínas E/genética , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Interleucina-6/metabolismo , Síndrome Metabólica/genética , Camundongos , Camundongos Knockout , Receptores CCR2/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The chemokine CCL2 (MCP-1) and its receptor CCR2 modulate leucocyte migration and T helper differentiation. CCL2 or CCR2 knockout (KO) mice have divergent phenotypes following infection with the intracellular parasite Leishmania major (L. major). Compared to wild-type (WT) mice, intradermally infected CCR2 KO mice in the L. major-resistant C57BL/6j background become susceptible and fail to generate protective Th1 responses. In contrast, subcutaneously infected CCL2 KO mice in the L. major-susceptible BALB/c background are resistant and exhibit reduced pathogenic Th2 responses. Here we explore two variables that may account for this contrasting outcome, namely background strain and route of infection. We found that the CCR2-null state, both in the BALB/c and the C57BL/6j background, was associated with increased susceptibility to intradermal or subcutaneous L. major infection. Notably, the CCL2-null state did not change the ability of C57BL/6j mice to mount protective responses following intradermal infection. Dual genetic inactivation of CCR2 and CCL2 in the L. major-resistant C57BL/6j background resulted in a shift to a susceptible phenotype analogous to that of CCR2 KO in the C57BL/6j background. We concluded that CCL2-independent effects of CCR2 are indispensable for the control of L. major infection and the generation of protective immune responses.