Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via beta2 integrin Mac-1.
OBJECTIVE
Receptor for advanced glycation end products (RAGE) is a cell surface molecule that binds a variety of ligands, including high mobility group box chromosomal protein 1 (HMGB-1), a potent proinflammatory cytokine. RAGE-ligand interaction leads to an inflammatory response. A truncated form of the receptor, soluble RAGE (sRAGE), has been suggested to function as a decoy abrogating cellular activation, but its endogenous activity is not fully understood. We undertook this study to assess the properties of sRAGE in vivo and in vitro and to analyze the role of sRAGE in HMGB-1-induced arthritis.


METHODS
Mice were injected intraarticularly with HMGB-1 and treated systemically with sRAGE prior to histologic joint evaluation. All animals were subjected to peritoneal lavage to assess the local effect of sRAGE treatment. For in vitro studies, mouse splenocytes were incubated with sRAGE followed by assessment of NF-kappaB activation and cytokine production. The chemotactic properties of sRAGE were investigated using in vitro migration assay.


RESULTS
Soluble RAGE was determined to have proinflammatory properties since it gave rise to production of interleukin-6, tumor necrosis factor alpha, and macrophage inflammatory protein 2. This effect was triggered by interaction with leukocyte beta2 integrin Mac-1 and was mediated via NF-kappaB. Systemic treatment with sRAGE significantly down-regulated HMGB-1-triggered arthritis, but the observed effect was due to a deviation of the inflammatory response from the joint to the peritoneal cavity rather than a genuine antiinflammatory effect. Apart from its proinflammatory properties, sRAGE was proven to act as a chemotactic stimulus for neutrophils.


CONCLUSIONS
We conclude that sRAGE interacts with Mac-1, thereby acting as an important proinflammatory and chemotactic molecule.
Pullerits
Rille
R
Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. Rille.Pullerits@rheuma.gu.se
Brisslert
Mikael
M
Jonsson
Ing-Marie
IM
Tarkowski
Andrej
A
D000818:Animals; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D007274:Injections, Intraperitoneal; D016177:Macrophage-1 Antigen / Q000096:biosynthesis*; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic