Receptor for advanced glycation end-products (RAGE) modulates neutrophil adhesion and migration on glycoxidated extracellular matrix.
AGEs (advanced glycation end-products) accumulate in collagen molecules during uraemia and diabetes, two diseases associated with high susceptibility to bacterial infection. Because neutrophils bind to collagen during their locomotion in extravascular tissue towards the infected area we investigated whether glycoxidation of collagen (AGE-collagen) alters neutrophil migration. Type I collagen extracted from rat tail tendons was used for in vitro glycoxidation (AGE-collagen). Neutrophils were obtained from peripheral blood of healthy adult volunteers and were used for the in vitro study of adhesion and migration on AGE- or control collagen. Glycoxidation of collagen increased adhesion of neutrophils to collagen surfaces. Neutrophil adhesion to AGE-collagen was inhibited by a rabbit anti-RAGE (receptor for AGEs) antibody and by PI3K (phosphoinositide 3-kinase) inhibitors. No effect was observed with ERK (extracellular-signal-regulated kinase) or p38 MAPK (mitogen-activated protein kinase) inhibitors. AGE-collagen was able to: (i) induce PI3K activation in neutrophils, and (ii) inhibit chemotaxis and chemokinesis of chemoattractant-stimulated neutrophils. Finally, we found that blocking RAGE with anti-RAGE antibodies or inhibiting PI3K with PI3K inhibitors restored fMLP (N-formylmethionyl-leucyl-phenylalanine)-induced neutrophil migration on AGE-collagen. These results show that RAGE and PI3K 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. As neutrophils rely on their ability to move to perform their function as the first line of defence against bacterial invasion, glycoxidation of collagen may participate in the suppression of normal host defence in patients with diabetes and uraemia.
Touré
Fatouma
F
Laboratory of Biochemistry and Molecular Biology, CNRS UMR 6198, F-51095 Reims, France.
Zahm
Jean-Marie
JM
Garnotel
Roselyne
R
Lambert
Elise
E
Bonnet
Noel
N
Schmidt
Ann Marie
AM
Vitry
Fabien
F
Chanard
Jacques
J
Gillery
Philippe
P
Rieu
Philippe
P
D000328:Adult; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D003600:Cytosol / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D013710:Tendons
D000906:Antibodies; D010455:Peptides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C065738:MLCK peptide