Systemic Inflammation in Metabolic Syndrome: Increased Platelet and Leukocyte Activation, and Key Role of CX3CL1/CX3CR1 and CCL2/CCR2 Axes in Arterial Platelet-Proinflammatory Monocyte Adhesion.

José T Real,Patrice Marques,Juan F Ascaso,Esther Benito,Laura Piqueras,Maria-Jesus Sanz,Sergio Martinez-Hervás,Elena Domingo,Aida Collado

doi:10.3390/jcm8050708

Abstract

Background: Metabolic syndrome is associated with low-grade systemic inflammation, which is a key driver of premature atherosclerosis. We characterized immune cell behavior in metabolic syndrome, its consequences, and the potential involvement of the CX3CL1/CX3CR1 and CCL2/CCR2 chemokine axes. Methods: Whole blood from 18 patients with metabolic syndrome and 21 age-matched controls was analyzed by flow cytometry to determine the leukocyte immunophenotypes, activation, platelet-leukocyte aggregates, and CX3CR1 expression. ELISA determined the plasma marker levels. Platelet-leukocyte aggregates adhesion to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium and the role of CX3CL1/CX3CR1 and CCL2/CCR2 axes was investigated with the parallel-plate flow chamber. Results: When compared with the controls, the metabolic syndrome patients presented greater percentages of eosinophils, CD3+ T lymphocytes, Mon2/Mon3 monocytes, platelet-eosinophil and -lymphocyte aggregates, activated platelets, neutrophils, eosinophils, monocytes, and CD8+ T cells, but lower percentages of Mon1 monocytes. Patients had increased circulating interleukin-8 (IL-8) and TNFα levels and decreased IL-4. CX3CR1 up-regulation in platelet-Mon1 monocyte aggregates in metabolic syndrome patients led to increased CX3CR1/CCR2-dependent platelet-Mon1 monocyte adhesion to dysfunctional arterial endothelium. Conclusion: We provide evidence of generalized immune activation in metabolic syndrome. Additionally, CX3CL1/CX3CR1 or CCL2/CCR2 axes are potential candidates for therapeutic intervention in cardiovascular disorders in metabolic syndrome patients, as their blockade impairs the augmented arterial platelet-Mon1 monocyte aggregate adhesiveness, which is a key event in atherogenesis.

Highlights

Cardiovascular disease (CVD), especially coronary heart disease and stroke, are the main causes of mortality in most European countries [1], and atherosclerosis is the principal contributor to the pathogenesis of myocardial and cerebral ischemic disorders
Platelet-leukocyte aggregates adhesion to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium and the role of CX3CL1/CX3CR1 and CCL2/CCR2 axes was investigated with the parallel-plate flow chamber
As increased circulating levels of TNFα have been detected in metabolic syndrome patients [12,15], which can up-regulate CX3CL1 expression and promote the generation and release of CCL2 [30,31], we investigated the role of CX3CL1/CX3CR1 and CCL2/CCR2 axes in platelet-leukocyte and leukocyte adhesion to the dysfunctional arterial endothelium in a metabolic syndrome model

Summary

Introduction

Cardiovascular disease (CVD), especially coronary heart disease and stroke, are the main causes of mortality in most European countries [1], and atherosclerosis is the principal contributor to the pathogenesis of myocardial and cerebral ischemic disorders. The diagnosis of metabolic syndrome is made when at least three of the five following criteria are met: (1) abdominal obesity; (2) arterial hypertension; (3) dysglycemia; (4) hypertriglyceridemia; and, (5) low high-density lipoprotein (HDL) cholesterol levels [4] These pathophysiological changes can lead to oxidative stress and inflammation, which increases the risk for atherosclerosis and CVD [5,6,7,8,9,10]. CX3CL1/CX3CR1 or CCL2/CCR2 axes are potential candidates for therapeutic intervention in cardiovascular disorders in metabolic syndrome patients, as their blockade impairs the augmented arterial platelet-Mon monocyte aggregate adhesiveness, which is a key event in atherogenesis

Methods

Results

Conclusion