The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta2microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis.
An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta2microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta2M. We demonstrate here that the interaction of AGE-beta2M with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of dialysis-related amyloidosis, is mediated by the receptor for AGEs, or RAGE. 125I-AGE-beta2M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (Kd approximately 53.5 and approximately 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade. AGE-beta2M-mediated monocyte chemotaxis was prevented by excess sRAGE or anti-RAGE IgG. Induction of tumor necrosis factor-alpha (TNF) expression by MPs exposed to AGE-beta2M resulted from engagement of RAGE, as appearances of TNF transcripts and TNF antigen release into culture supernatants were prevented by addition of sRAGE, a process mediated, at least in part, by oxidant stress. AGE-beta2M reduced cytochrome c and the elaboration of TNF by MPs was inhibited by N-acetylcysteine. Consistent with these data, immunohistochemical studies of AGE-laden amyloid deposits of a long-term hemodialysis patient revealed positive staining for RAGE in the MPs infiltrating these lesions. These data indicate that RAGE is a central binding site for AGEs formed in vivo and suggest that AGE-beta2M-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of long-term hemodialysis patients, a process which may ultimately lead to bone and joint destruction.
Miyata
T
T
Department of Internal Medicine, Branch Hospital, Nagoya University School of Medicine, Japan.
Hori
O
O
Zhang
J
J
Yan
S D
SD
Ferran
L
L
Iida
Y
Y
Schmidt
A M
AM
D000686:Amyloidosis / Q000209:etiology*; D015703:Antigens, CD / Q000302:isolation & purification; D015214:Antigens, Differentiation, Myelomonocytic / Q000302:isolation & purification; D002465:Cell Movement; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007592:Joint Diseases / Q000209:etiology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010586:Phagocytes / Q000378:metabolism*; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D006435:Renal Dialysis / Q000009:adverse effects; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D001613:beta 2-Microglobulin / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; C067980:CD68 antigen, human; D000097382:CD68 Molecule