RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.
S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environmental cues. We report here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular activation and tissue injury.
College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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MA
Hofmann
S
S
Drury
C
C
Fu
W
W
Qu
A
A
Taguchi
Y
Y
Lu
C
C
Avila
N
N
Kambham
A
A
Bierhaus
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P
Nawroth
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Neurath
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T
Slattery
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Beach
J
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McClary
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Nagashima
J
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Morser
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D
Stern
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Schmidt
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D003092:Colitis / Q000276:immunology; D018076:DNA, Complementary; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D010586:Phagocytes / Q000166:cytology / Q000276:immunology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*; D009418:S100 Proteins / Q000235:genetics / Q000276:immunology*; D000067616:S100A12 Protein
D018076:DNA, Complementary; D008565:Membrane Proteins; D010455:Peptides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human