Receptor for Advanced Glycation end products (RAGE) modulates neutrophil adhesion and migration on Glycoxidated extracellular matrix
Résumé
Introduction: Advanced glycation end products (AGEs) accumulate in collagen molecules during uremia and diabetes, two diseases associated with high susceptibility to bacterial infection. Because neutrophils bind to collagen during their locomotion in extravascular tissue toward the infected area, we investigated whether glycoxidation of collagen (AGE-collagen) alters neutrophil migration. Experimental design: Type I collagen extracted from rat tail tendons was used for in vitro glycoxidation (AGE-collagen). Neutrophils were obtained from peripheral blood of healthy adults volunteers and used for in vitro study of adhesion and migration on AGE- or control Collagen. Results: Glycoxidation of collagen increased adhesion of neutrophils to collagen surfaces. Neutrophil adhesion to AGE-collagen was inhibited by rabbit anti-RAGE antibody and by PI3-Kinase inhibitors. No effect was observed with MAPK/ERK and MAPK/P38 inhibitors. AGE-collagen was able to: 1/ induce PI3-Kinase activation in neutrophils and 2/ inhibit chemotaxis and chemokinesis of chemoattractant-stimulated neutrophils. Finally, we found that blocking RAGE with anti-RAGE antibodies or inhibiting PI3-kinase with PI3-Kinase inhibitors restored f-MLP-induced neutrophil migration on AGE-collagen. Discussion: These results show that RAGE and PI3-Kinase modulate adhesion and migration rate of neutrophils on AGE-Collagen. Modulation of adhesiveness may account for the change in neutrophil migration rate on AGE-collagen. Since neutrophils rely on their ability to move to perform their function as the first line of defense against bacterial invasion, glycoxidation of collagen may participate in the suppression of normal host defense in diabetic and uremic patients.
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