RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs).
The accumulation of advanced glycation end products (AGEs) in the tissue and serum of subjects with diabetes has been linked to the pathogenesis of vascular complications. Because diabetes may be also complicated by increased susceptibility to recurrent infection, we investigated the effects of AGEs on human neutrophils, because their burst of activity immediately upon engagement of pathogens or other inflammatory triggers is critical to host response. We demonstrate the presence of receptor for advanced glycation end products (RAGE) at the message and protein levels. We also demonstrate that AGE albumin (but not control albumin) binds with high affinity to human neutrophils (K(d) of 3.7 +/- 0.4 nM). The binding was blocked almost completely by excess soluble RAGE, anti-RAGE antibodies, or antibodies to CML-modified albumin. AGE albumin induced a dose-dependent increase in intracellular-free calcium as well as actin polymerization. Further, AGE albumin inhibited transendothelial migration and Staphylococcus aureus-induced but not fMLP-induced production of reactive oxygen metabolite. Moreover, although AGE albumin enhanced neutrophil phagocytosis of S. aureus, it inhibited bacterial killing. We conclude that functional RAGE is present on the plasma membrane of human neutrophils and is linked to Ca(2)(+) and actin polymerization, and engagement of RAGE impairs neutrophil functions.
Collison
Kate S
KS
Biological & Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
Parhar
Ranjit S
RS
Saleh
Soad S
SS
Meyer
Brian F
BF
Kwaasi
Aaron A
AA
Hammami
Muhammad M
MM
Schmidt
Ann Marie
AM
Stern
David M
DM
Al-Mohanna
Futwan A
FA
D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism; D000075462:Serum Albumin, Human
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012709:Serum Albumin; C109748:advanced glycation end products-human serum albumin; D000075462:Serum Albumin, Human