sRAGE induces human monocyte survival and differentiation.
The receptor for advanced glycation end products (RAGE) is produced either as a transmembrane or soluble form (sRAGE). Substantial evidence supports a role for RAGE and its ligands in disease. sRAGE is reported to be a competitive, negative regulator of membrane RAGE activation, inhibiting ligand binding. However, some reports indicate that sRAGE is associated with inflammatory disease. We sought to define the biological function of sRAGE on inflammatory cell recruitment, survival, and differentiation in vivo and in vitro. To test the in vivo impact of sRAGE, the recombinant protein was intratracheally administered to mice, which demonstrated monocyte- and neutrophil-mediated lung inflammation. We also observed that sRAGE induced human monocyte and neutrophil migration in vitro. Human monocytes treated with sRAGE produced proinflammatory cytokines and chemokines. Our data demonstrated that sRAGE directly bound human monocytes and monocyte-derived macrophages. Binding of sRAGE to monocytes promoted their survival and differentiation to macrophages. Furthermore, sRAGE binding to cells increased during maturation, which was similar in freshly isolated mouse monocytes compared with mature tissue macrophages. Because sRAGE activated cell survival and differentiation, we examined intracellular pathways that were activated by sRAGE. In primary human monocytes and macrophages, sRAGE treatment activated Akt, Erk, and NF-kappaB, and their activation appeared to be critical for cell survival and differentiation. Our data suggest a novel role for sRAGE in monocyte- and neutrophil-mediated inflammation and mononuclear phagocyte survival and differentiation.
Wang
Yijie
Y
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Wang
Hongmei
H
Piper
Melissa G
MG
McMaken
Sara
S
Mo
Xiaokui
X
Opalek
Judy
J
Schmidt
Ann Marie
AM
Marsh
Clay B
CB
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage* / Q000502:physiology*; D012995:Solubility; D015854:Up-Regulation / Q000276:immunology
D061945:Caspase Inhibitors; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; D053148:Caspase 3