Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via beta2 integrin Mac-1.
TLDR
It is concluded that sRAGE interacts with Mac-1, thereby acting as an important proinflammatory and chemotactic molecule and was proven to act as a Chemotactic stimulus for neutrophils.Abstract:
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-κB 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 α, and macrophage inflammatory protein 2. This effect was triggered by interaction with leukocyte β2 integrin Mac-1 and was mediated via NF-κB. 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.
Conclusion
We conclude that sRAGE interacts with Mac-1, thereby acting as an important proinflammatory and chemotactic molecule.read more
Citations
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Journal ArticleDOI
HMGB1 in Health and Disease
Rui Kang,Ruochan Chen,Qiuhong Zhang,Wen Hou,Sha Wu,Lizhi Cao,Jin Huang,Yan Yu,Xue Gong Fan,Zhengwen Yan,Zhengwen Yan,Xiaofang Sun,Haichao Wang,Qingde Wang,Allan Tsung,Timothy R. Billiar,Herbert J. Zeh,Michael T. Lotze,Daolin Tang +18 more
TL;DR: High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside thecell as the prototypic damage associated molecular pattern molecule (DAMP).
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TL;DR: The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex, and sits in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress.
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TL;DR: Despite broad experimental evidence for the role of RAGES in chronic disease, knowledge of its physiological function is still missing, limiting predictions about safety of long-term inhibition of RAGE’s ligand interaction in chronic diseases.
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Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1.
Roberto Romero,Tinnakorn Chaiworapongsa,Zeynep Alpay Savasan,Yi Xu,Youssef Hussein,Zhong Dong,Juan Pedro Kusanovic,Chong Jai Kim,Sonia S. Hassan +8 more
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HMGB1 as biomarker and drug target
Emilie Venereau,Federica De Leo,Rosanna Mezzapelle,Giorgia Careccia,Giovanna Musco,Marco Bianchi +5 more
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References
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HMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Haichao Wang,Ona Bloom,Minghuang Zhang,Jaideep M. Vishnubhakat,Michael Ombrellino,Jiantu Che,Asia Frazier,Huan Yang,Svetlana Ivanova,Lyudmila V. Borovikova,Kirk R. Manogue,Eugen Faist,Edward Abraham,Jan Andersson,Ulf Andersson,Patricia E. Molina,Naji N. Abumrad,Andrew E. Sama,Kevin J. Tracey +18 more
TL;DR: High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1, and showed increased serum levels after endotoxin exposure, suggesting that this protein warrants investigation as a therapeutic target.
Journal ArticleDOI
RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.
Marion A. Hofmann,Steven Drury,Caifeng Fu,Wu Qu,Akihiko Taguchi,Yan Lu,Cecilia Avila,Neeraja Kambham,Angelika Bierhaus,Peter P. Nawroth,Markus F. Neurath,Timothy Slattery,Dale L. Beach,John McClary,Mariko Nagashima,John Morser,David M. Stern,Ann Marie Schmidt +17 more
TL;DR: It is reported 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.
Journal ArticleDOI
The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses
TL;DR: These features of RAGE allow the receptor to propagate cellular dysfunction in a number of pathophysiologically relevant situations, most often dictated by the formation and persistence of ligands in the tissues.
Journal ArticleDOI
The Receptor for Advanced Glycation End Products (RAGE) Is a Cellular Binding Site for Amphoterin MEDIATION OF NEURITE OUTGROWTH AND CO-EXPRESSION OF RAGE AND AMPHOTERIN IN THE DEVELOPING NERVOUS SYSTEM
Osamu Hori,Jerold Brett,Timothy Slattery,Rong Cao,Jinghua Zhang,Jing Xian Chen,Mariko Nagashima,Erik R. Lundh,Sharmila Vijay,Di Nitecki,John Morser,David M. Stern,Ann Marie Schmidt +12 more
TL;DR: The receptor for advanced glycation end products (RAGE), a newly-identified member of the immunoglobulin superfamily, mediates interactions of AGE-modified proteins with endothelium and other cell types.
Journal ArticleDOI
Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.
Lisa Park,Kathleen G. Raman,Kenneth J. Lee,Yan Lu,Luis J. Ferran,Wing Sun Chow,David M. Stern,Ann Marie Schmidt +7 more
TL;DR: Findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.