The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily, capable of binding a broad repertoire of ligands. RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF- B as well as increased expression of cytokines, chemokines, and adhesion molecules. These effects endow RAGE with the role in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation. RAGE signaling and downstream pathways have been implicated in a wide spectrum of inflammatory-related pathologic conditions such as arteriosclerosis, Alzheimer's disease, arthritis, acute respiratory failure, and sepsis. Despite the significant progress in other RAGE studies, the functional importance of the receptor in clinical situations and inflammatory diseases still remains to be fully realized. In this review, we will summarize current understandings and lines of evidence on the molecular mechanisms through which RAGE signaling contributes to the pathogenesis of the aforementioned inflammation-associated conditions. 1. Introduction The receptor for advanced glycation end products (RAGE), which belongs to the immunoglobulin superfamily, was first identified and described in terms of its ability to bind advanced glycation end products (AGEs) [1, 2]. This explains the choice of “RAGE” to name this receptor. Due to the ability of RAGE to recognize three-dimensional structures rather than specific amino acid sequences, RAGE is capable of engaging a diverse class of ligands that lack sequence similarities. Because of this feature, this multiligand receptor can therefore be considered a pattern-recognition receptor (PRR) [1, 3]. Ligands that have been found to be recognized by RAGE include AGEs [1], amyloid β-peptide [4], DNA binding protein high mobility group box-1 (HMGBl)/amphoterin [5], and S100/calgranulins [6]. In humans and mice, the gene encoding RAGE is located on chromosome 6 close to major histocompatibility complex III (MHC class III), in the vicinity of the genes for lymphotoxin, tumour necrosis factor (TNF), and the homeobox gene HOX12 [7, 8]. Translation of the mRNA transcribed from this human RAGE gene (~1.4？kb) results in a protein of 404 amino acids with a molecular mass of about 55？kDa [2]. RAGE is composed of a single hydrophobic transmembrane-spanning domain, a highly charged cytosolic tail, and an extracellular region (Figure 1). This extracellular region consists of one N-terminal V-type
References
[1]
A. M. Schmidt, M. Vianna, M. Gerlach et al., “Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface,” The Journal of Biological Chemistry, vol. 267, no. 21, pp. 14987–14997, 1992.
[2]
M. Neeper, A. M. Schmidt, J. Brett et al., “Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins,” The Journal of Biological Chemistry, vol. 267, no. 21, pp. 14998–15004, 1992.
[3]
A. M. Schmidt, S. D. Yan, S. F. Yan, and D. M. Stern, “The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses,” Journal of Clinical Investigation, vol. 108, no. 7, pp. 949–955, 2001.
[4]
S. D. Yan, H. Zhu, J. Fu et al., “Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5296–5301, 1997.
[5]
O. Hori, J. Brett, T. Slattery et al., “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,” The Journal of Biological Chemistry, vol. 270, no. 43, pp. 25752–25761, 1995.
[6]
M. A. Hofmann, S. Drury, C. Fu et al., “RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides,” Cell, vol. 97, no. 7, pp. 889–901, 1999.
[7]
K. Sugaya, T. Fukagawa, K.-I. Matsumoto et al., “Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3,” Genomics, vol. 23, no. 2, pp. 408–419, 1994.
[8]
P. Malherbe, J. G. Richards, H. Gaillard et al., “cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein,” Molecular Brain Research, vol. 71, no. 2, pp. 159–170, 1999.
[9]
C. Bopp, A. Bierhaus, S. Hofer et al., “Bench-to-bedside review: the inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis,” Critical Care, vol. 12, no. 1, article 201, 2008.
[10]
B. M. Dattilo, G. Fritz, E. Leclerc, C. W. Vander Kooi, C. W. Heizmann, and W. J. Chazin, “The extracellular region of the receptor for advanced glycation end products is composed of two independent structural units,” Biochemistry, vol. 46, no. 23, pp. 6957–6970, 2007.
[11]
T. Ostendorp, E. Leclerc, A. Galichet et al., “Structural and functional insights into RAGE activation by multimeric S100B,” The EMBO Journal, vol. 26, no. 16, pp. 3868–3878, 2007.
[12]
J. Brett, A. M. Schmidt, S. D. Y. Shi Du Yan et al., “Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues,” The American Journal of Pathology, vol. 143, no. 6, pp. 1699–1712, 1993.
[13]
A. M. Schmidt, S. D. Y. Shi Du Yan, J. Brett, R. Mora, R. Nowygrod, and D. Stern, “Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products,” Journal of Clinical Investigation, vol. 91, no. 5, pp. 2155–2168, 1993.
[14]
H. J. Huttunen, C. Fages, and H. Rauvala, “Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-κB require the cytoplasmic domain of the receptor but different downstream signaling pathways,” The Journal of Biological Chemistry, vol. 274, no. 28, pp. 19919–19924, 1999.
[15]
H. Fehrenbach, M. Kasper, T. Tschernig, M. S. Shearman, D. Schuh, and M. Müller, “Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung,” Cellular and Molecular Biology, vol. 44, no. 7, pp. 1147–1157, 1998.
[16]
F. Katsuoka, Y. Kawakami, T. Arai et al., “Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene,” Biochemical and Biophysical Research Communications, vol. 238, no. 2, pp. 512–516, 1997.
[17]
K. A. Sterenczak, I. Nolte, and H. Murua Escobar, “RAGE splicing variants in mammals,” Methods in Molecular Biology, vol. 963, pp. 265–276, 2013.
[18]
C. Schlueter, S. Hauke, A. M. Flohr, P. Rogalla, and J. Bullerdiek, “Tissue-specific expression patterns of the RAGE receptor and its soluble forms—a result of regulated alternative splicing?” Biochimica et Biophysica Acta, vol. 1630, no. 1, pp. 1–6, 2003.
[19]
H. Yonekura, Y. Yamamoto, S. Sakurai et al., “Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury,” Biochemical Journal, vol. 370, no. 3, pp. 1097–1109, 2003.
[20]
B. I. Hudson, A. M. Carter, E. Harja et al., “Identification, classification, and expression of RAGE gene splice variants,” The FASEB Journal, vol. 22, no. 5, pp. 1572–1580, 2008.
[21]
Q. Ding and J. N. Keller, “Evaluation of rage isoforms, ligands, and signaling in the brain,” Biochimica et Biophysica Acta, vol. 1746, no. 1, pp. 18–27, 2005.
[22]
Q. Ding and J. N. Keller, “Splice variants of the receptor for advanced glycosylation end products (RAGE) in human brain,” Neuroscience Letters, vol. 373, no. 1, pp. 67–72, 2005.
[23]
I. H. Park, S. I. Yeon, J. H. Youn et al., “Expression of a novel secreted splice variant of the receptor for advanced glycation end products (RAGE) in human brain astrocytes and peripheral blood mononuclear cells,” Molecular Immunology, vol. 40, no. 16, pp. 1203–1211, 2004.
[24]
L. E. Hanford, J. J. Enghild, Z. Valnickova et al., “Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE),” The Journal of Biological Chemistry, vol. 279, no. 48, pp. 50019–50024, 2004.
[25]
L. Park, K. G. Raman, K. J. Lee et al., “Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts,” Nature Medicine, vol. 4, no. 9, pp. 1025–1031, 1998.
[26]
B. I. Hudson, L. G. Bucciarelli, T. Wendt et al., “Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders,” Archives of Biochemistry and Biophysics, vol. 419, no. 1, pp. 80–88, 2003.
[27]
C. Cheng, K. Tsuneyama, R. Kominami et al., “Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs,” Modern Pathology, vol. 18, no. 10, pp. 1385–1396, 2005.
[28]
A. Raucci, S. Cugusi, A. Antonelli et al., “A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10),” The FASEB Journal, vol. 22, no. 10, pp. 3716–3727, 2008.
[29]
L. Zhang, M. Bukulin, E. Kojro et al., “Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases,” The Journal of Biological Chemistry, vol. 283, no. 51, pp. 35507–35516, 2008.
[30]
A. Bierhaus, D. M. Stern, and P. P. Nawroth, “RAGE in inflammation: a new therapeutic target?” Current Opinion in Investigational Drugs, vol. 7, no. 11, pp. 985–991, 2006.
[31]
R. Clynes, B. Moser, S. F. Yan, R. Ramasamy, K. Herold, and A. M. Schmidt, “Receptor for AGE (RAGE): weaving tangled webs within the inflammatory response,” Current Molecular Medicine, vol. 7, no. 8, pp. 743–751, 2007.
[32]
K. Herold, B. Moser, Y. Chen et al., “Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress,” Journal of Leukocyte Biology, vol. 82, no. 2, pp. 204–212, 2007.
[33]
K. S. Collison, R. S. Parhar, S. S. Saleh et al., “RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs),” Journal of Leukocyte Biology, vol. 71, no. 3, pp. 433–444, 2002.
[34]
C. Gebhardt, A. Riehl, M. Durchdewald et al., “RAGE signaling sustains inflammation and promotes tumor development,” Journal of Experimental Medicine, vol. 205, no. 2, pp. 275–285, 2008.
[35]
Y. Chen, E. M. Akirav, W. Chen et al., “RAGE ligation affects T cell activation and controls T cell differentiation,” Journal of Immunology, vol. 181, no. 6, pp. 4272–4278, 2008.
[36]
T. Chavakis, A. Bierhaus, N. Al-Fakhri et al., “The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment,” Journal of Experimental Medicine, vol. 198, no. 10, pp. 1507–1515, 2003.
[37]
V. V. Orlova, E. Y. Choi, C. Xie et al., “A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin,” The EMBO Journal, vol. 26, no. 4, pp. 1129–1139, 2007.
[38]
C. Gebhardt, J. Németh, P. Angel, and J. Hess, “S100A8 and S100A9 in inflammation and cancer,” Biochemical Pharmacology, vol. 72, no. 11, pp. 1622–1631, 2006.
[39]
D. Foell, H. Wittkowski, T. Vogl, and J. Roth, “S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules,” Journal of Leukocyte Biology, vol. 81, no. 1, pp. 28–37, 2007.
[40]
M. E. Bianchi and A. A. Manfredi, “High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity,” Immunological Reviews, vol. 220, no. 1, pp. 35–46, 2007.
[41]
A. Bierhaus, P. M. Humpert, M. Morcos et al., “Understanding RAGE, the receptor for advanced glycation end products,” Journal of Molecular Medicine, vol. 83, no. 11, pp. 876–886, 2005.
[42]
J. Li and A. M. Schmidt, “Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products,” The Journal of Biological Chemistry, vol. 272, no. 26, pp. 16498–16506, 1997.
[43]
A. M. Schmidt, S. D. Yan, S. F. Yan, and D. M. Stern, “The biology of the receptor for advanced glycation end products and its ligands,” Biochimica et Biophysica Acta, vol. 1498, no. 2-3, pp. 99–111, 2000.
[44]
A. Bierhaus, S. Schiekofer, M. Schwaninger et al., “Diabetes-associated sustained activation of the transcription factor nuclear factor-κB,” Diabetes, vol. 50, no. 12, pp. 2792–2808, 2001.
[45]
L. J. Sparvero, D. Asafu-Adjei, R. Kang et al., “RAGE (Receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation,” Journal of Translational Medicine, vol. 7, article 17, 2009.
[46]
R. Ramasamy, S. F. Yan, K. Herold, R. Clynes, and A. M. Schmidt, “Receptor for advanced glycation end products—fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis,” Annals of the New York Academy of Sciences, vol. 1126, pp. 7–13, 2008.
[47]
T. Bonaldi, F. Talamo, P. Scaffidi et al., “Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion,” The EMBO Journal, vol. 22, no. 20, pp. 5551–5560, 2003.
[48]
A. A. Manfredi, A. Capobianco, A. Esposito et al., “Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes,” Journal of Immunology, vol. 180, no. 4, pp. 2270–2275, 2008.
[49]
L. Lin, S. Park, and E. G. Lakatta, “RAGE signaling in inflammation and arterial aging,” Frontiers in Bioscience, vol. 14, no. 4, pp. 1403–1413, 2009.
[50]
J. Tian, A. M. Avalos, S.-Y. Mao et al., “Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE,” Nature Immunology, vol. 8, no. 5, pp. 487–496, 2007.
[51]
R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999.
[52]
A. Goldin, J. A. Beckman, A. M. Schmidt, and M. A. Creager, “Advanced glycation end products: sparking the development of diabetic vascular injury,” Circulation, vol. 114, no. 6, pp. 597–605, 2006.
[53]
G. Basta, A. M. Schmidt, and R. De Caterina, “Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes,” Cardiovascular Research, vol. 63, no. 4, pp. 582–592, 2004.
[54]
V. Scivittaro, M. B. Ganz, and M. F. Weiss, “AGEs induce oxidative stress and activate protein kinase C-β(II) in neonatal mesangial cells,” The American Journal of Physiology, vol. 278, no. 4, pp. F676–F683, 2000.
[55]
M.-P. Wautier, O. Chappey, S. Corda, D. M. Stern, A. M. Schmidt, and J.-L. Wautier, “Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE,” The American Journal of Physiology, vol. 280, no. 5, pp. E685–E694, 2001.
[56]
G. Basta, G. Lazzerini, M. Massaro et al., “Advanced glycation end products activate endothelium through signal-transduction receptor RAGE a mechanism for amplification of inflammatory responses,” Circulation, vol. 105, no. 7, pp. 816–822, 2002.
[57]
U. Siebenlist, G. Franzoso, and K. Brown, “Structure, regulation and function of NF-κB,” Annual Review of Cell Biology, vol. 10, pp. 405–455, 1994.
[58]
A. M. Schmidt, O. Hori, J. X. C. Jing Xian Chen et al., “Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice: a potential mechanism for the accelerated vasculopathy of diabetes,” Journal of Clinical Investigation, vol. 96, no. 3, pp. 1395–1403, 1995.
[59]
A. J. Lusis, “Atherosclerosis,” Nature, vol. 407, no. 6801, pp. 233–241, 2000.
[60]
P.-A. Jansson, “Endothelial dysfunction in insulin resistance and type 2 diabetes,” Journal of Internal Medicine, vol. 262, no. 2, pp. 173–183, 2007.
[61]
E. Harja, D.-X. Bu, B. I. Hudson et al., “Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice,” Journal of Clinical Investigation, vol. 118, no. 1, pp. 183–194, 2008.
[62]
C. Esposito, H. Gerlach, J. Brett, D. Stern, and H. Vlassara, “Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties,” Journal of Experimental Medicine, vol. 170, no. 4, pp. 1387–1407, 1989.
[63]
A. Bierhaus, T. Illmer, M. Kasper et al., “Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE,” Circulation, vol. 96, no. 7, pp. 2262–2271, 1997.
[64]
D. Aronson and E. J. Rayfield, “How hyperglycemia promotes atherosclerosis: molecular mechanisms,” Cardiovascular Diabetology, vol. 1, article 1, 2002.
[65]
R. Piga, Y. Naito, S. Kokura, O. Handa, and T. Yoshikawa, “Short-term high glucose exposure induces monocyte-endothelial cells adhesion and transmigration by increasing VCAM-1 and MCP-1 expression in human aortic endothelial cells,” Atherosclerosis, vol. 193, no. 2, pp. 328–334, 2007.
[66]
M. Kirstein, J. Brett, S. Radoff, S. Ogawa, D. Stern, and H. Vlassara, “Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 22, pp. 9010–9014, 1990.
[67]
M. Kirstein, C. Aston, R. Hintz, and H. Vlassara, “Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins,” Journal of Clinical Investigation, vol. 90, no. 2, pp. 439–446, 1992.
[68]
T. Miyata, R. Inagi, Y. Iida et al., “Involvement of β2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-α and interleukin-1,” Journal of Clinical Investigation, vol. 93, no. 2, pp. 521–528, 1994.
[69]
Y. Iwashima, M. Eto, A. Hata et al., “Advanced glycation end products-induced gene expression of scavenger receptors in cultured human monocyte-derived macrophages,” Biochemical and Biophysical Research Communications, vol. 277, no. 2, pp. 368–380, 2000.
[70]
K. Isoda, E. J. Folco, K. Shimizu, and P. Libby, “AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL,” Atherosclerosis, vol. 192, no. 2, pp. 298–304, 2007.
[71]
N. Sakata, J. Meng, and S. Takebayashi, “Effects of advanced glycation end products on the proliferation and fibronectin production of smooth muscle cells,” Journal of Atherosclerosis and Thrombosis, vol. 7, no. 3, pp. 169–176, 2000.
[72]
T. Higashi, H. Sano, T. Saishoji et al., “The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells,” Diabetes, vol. 46, no. 3, pp. 463–472, 1997.
[73]
M. A. Reddy, S.-L. Li, S. Sahar et al., “Key role of Src kinase in S100B-induced activation of the receptor for advanced glycation end products in vascular smooth muscle cells,” The Journal of Biological Chemistry, vol. 281, no. 19, pp. 13685–13693, 2006.
[74]
T. Sakaguchi, S. F. Yan, S. D. Yan et al., “Central role of RAGE-dependent neointimal expansion in arterial restenosis,” Journal of Clinical Investigation, vol. 111, no. 7, pp. 959–972, 2003.
[75]
S. S. Shaw, A. M. Schmidt, A. K. Banes, X. Wang, D. M. Stern, and M. B. Marrero, “S100b-RAGE-mediated augmentation of angiotensin II-induced activation of JAK2 in vascular smooth muscle cells is dependent on PLD2,” Diabetes, vol. 52, no. 9, pp. 2381–2388, 2003.
[76]
Y. W. Yoon, T. S. Kang, B. K. Lee et al., “Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy,” Experimental and Molecular Medicine, vol. 40, no. 4, pp. 398–406, 2008.
[77]
Y. G. Wolf, L. M. Rasmussen, and E. Ruoslahti, “Antibodies against transforming growth factor-β1 suppress intimal hyperplasia in a rat model,” Journal of Clinical Investigation, vol. 93, no. 3, pp. 1172–1178, 1994.
[78]
B. Degryse, T. Bonaldi, P. Scaffidi et al., “The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells,” Journal of Cell Biology, vol. 152, no. 6, pp. 1197–1206, 2001.
[79]
A. Porto, R. Palumbo, M. Pieroni et al., “Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein,” The FASEB Journal, vol. 20, no. 14, pp. 2565–2566, 2006.
[80]
L. E. Hebert, P. A. Scherr, J. L. Bienias, D. A. Bennett, and D. A. Evans, “Alzheimer disease in the US population: prevalence estimates using the 2000 census,” Archives of Neurology, vol. 60, no. 8, pp. 1119–1122, 2003.
[81]
B. Muller-Hill and K. Beyreuther, “Molecular biology of Alzheimer's disease,” Annual Review of Biochemistry, vol. 58, pp. 287–307, 1989.
[82]
C. Supnet and I. Bezprozvanny, “The dysregulation of intracellular calcium in Alzheimer disease,” Cell Calcium, vol. 47, no. 2, pp. 183–189, 2010.
[83]
M. C. Miller, R. Tavares, C. E. Johanson et al., “Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease,” Brain Research, vol. 1230, pp. 273–280, 2008.
[84]
S. D. Yan, X. Chen, J. Fu et al., “RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease,” Nature, vol. 382, no. 6593, pp. 685–691, 1996.
[85]
A. Bierhaus and P. P. Nawroth, “Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications,” Diabetologia, vol. 52, no. 11, pp. 2251–2263, 2009.
[86]
M. P. Mattson and S. Camandola, “NF-κB in neuronal plasticity and neurodegenerative disorders,” Journal of Clinical Investigation, vol. 107, no. 3, pp. 247–254, 2001.
[87]
M. Guglielmotto, M. Aragno, E. Tamagno et al., “AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation,” Neurobiology of Aging, vol. 33, no. 1, pp. 196–e27, 2012.
[88]
V. Srikanth, A. Maczurek, T. Phan et al., “Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease,” Neurobiology of Aging, vol. 32, no. 5, pp. 763–777, 2011.
[89]
T. Valente, A. Gella, X. Fernàndez-Busquets, M. Unzeta, and N. Durany, “Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus,” Neurobiology of Disease, vol. 37, no. 1, pp. 67–76, 2010.
[90]
H. J. Cho, S. M. Son, S. M. Jin et al., “RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer's disease animal model,” The FASEB Journal, vol. 23, no. 8, pp. 2639–2649, 2009.
[91]
N. Origlia, M. Righi, S. Capsoni et al., “Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-β-mediated cortical synaptic dysfunction,” Journal of Neuroscience, vol. 28, no. 13, pp. 3521–3530, 2008.
[92]
N. Origlia, S. Capsoni, A. Cattaneo et al., “Aβ-dependent inhibition of LTP in different intracortical circuits of the visual cortex: the role of RAGE,” Journal of Alzheimer's Disease, vol. 17, no. 1, pp. 59–68, 2009.
[93]
B. Kuhla, C. Loske, S. Garcia De Arriba, R. Schinzel, J. Huber, and G. Münch, “Differential effects of “Advanced glycation endproducts” and β-amyloid peptide on glucose utilization and ATP levels in the neuronal cell line SH-SY5Y,” Journal of Neural Transmission, vol. 111, no. 3, pp. 427–439, 2004.
[94]
S. D. Yan, A. Roher, M. Chaney, B. Zlokovic, A. M. Schmidt, and D. Stern, “Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid β-peptide,” Biochimica et Biophysica Acta, vol. 1502, no. 1, pp. 145–157, 2000.
[95]
K. Takuma, F. Fang, W. Zhang et al., “RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 47, pp. 20021–20026, 2009.
[96]
S. Fuller, M. Steele, and G. Münch, “Activated astroglia during chronic inflammation in Alzheimer's disease—do they neglect their neurosupportive roles?” Mutation Research, vol. 690, no. 1-2, pp. 40–49, 2010.
[97]
F. Fang, L.-F. Lue, S. Yan et al., “RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease,” The FASEB Journal, vol. 24, no. 4, pp. 1043–1055, 2010.
[98]
J. B. Mackic, J. Bading, J. Ghiso et al., “Circulating amyloid-β peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions,” Vascular Pharmacology, vol. 38, no. 6, pp. 303–313, 2002.
[99]
C. L. Martel, J. B. Mackic, J. G. McComb, J. Ghiso, and B. V. Zlokovic, “Blood-brain barrier uptake of the 40 and 42 amino acid sequences of circulating Alzheimer's amyloid β in guinea pigs,” Neuroscience Letters, vol. 206, no. 2-3, pp. 157–160, 1996.
[100]
R. Deane, S. D. Yan, R. K. Submamaryan et al., “RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain,” Nature Medicine, vol. 9, no. 7, pp. 907–913, 2003.
[101]
T. Malm, M. Koistinaho, A. Muona, J. Magga, and J. Koistinaho, “The role and therapeutic potential of monocytic cells in Alzheimer's disease,” GLIA, vol. 58, no. 8, pp. 889–900, 2010.
[102]
R. Giri, S. Selvaraj, C. A. Miller et al., “Effect of endothelial cell polarity on β-amyloid-induced migration of monocytes across normal and AD endothelium,” The American Journal of Physiology, vol. 283, no. 3, pp. C895–C904, 2002.
[103]
R. F. Loeser, “Age-related changes in the musculoskeletal system and the development of osteoarthritis,” Clinics in Geriatric Medicine, vol. 26, no. 3, pp. 371–386, 2010.
[104]
M. Feldmann, F. M. Brennan, and R. N. Maini, “Rheumatoid arthritis,” Cell, vol. 85, no. 3, pp. 307–310, 1996.
[105]
S. Drinda, S. Franke, M. Rüster et al., “Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis,” Rheumatology International, vol. 25, no. 6, pp. 411–413, 2005.
[106]
M. M. C. Steenvoorden, T. W. J. Huizinga, N. Verzijl et al., “Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes,” Arthritis and Rheumatism, vol. 54, no. 1, pp. 253–263, 2006.
[107]
K. Sunahori, M. Yamamura, J. Yamana, K. Takasugi, M. Kawashima, and H. Makino, “Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 54, no. 1, pp. 97–104, 2006.
[108]
S. Drinda, S. Franke, C. C. Canet et al., “Identification of the advanced glycation end products Nε-carboxymethyllysine in the synovial tissue of patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 61, no. 6, pp. 488–492, 2002.
[109]
R. F. Loeser, R. R. Yammani, C. S. Carlson et al., “Articular chondrocytes express the receptor for advanced glycation end products: potential role in osteoarthritis,” Arthritis and Rheumatism, vol. 52, no. 8, pp. 2376–2385, 2005.
[110]
N. Verzijl, J. DeGroot, E. Oldehinkel et al., “Age-related accumulation of Maillard reaction products in human articular cartilage collagen,” Biochemical Journal, vol. 350, no. 2, pp. 381–387, 2000.
[111]
R. R. Yammani, C. S. Carlson, A. R. Bresnick, and R. F. Loeser, “Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: role of the receptor for advanced glycation end products,” Arthritis and Rheumatism, vol. 54, no. 9, pp. 2901–2911, 2006.
[112]
J. R. Chen, M. Takahashi, M. Suzuki, K. Kushida, S. Miyamoto, and T. Inoue, “Comparison of the concentrations of pentosidine in the synovial fluid, serum and urine of patients with rheumatoid arthritis and osteoarthritis,” Rheumatology, vol. 38, no. 12, pp. 1275–1278, 1999.
[113]
R. A. Bank, M. T. Bayliss, F. P. J. G. Lafeber, A. Maroudas, and J. M. Tekoppele, “Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage: the age-related increase in Non-Enzymatic Glycation affects biomechanical properties of cartilage,” Biochemical Journal, vol. 330, no. 1, pp. 345–351, 1998.
[114]
N. Verzijl, J. DeGroot, C. B. Zaken et al., “Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis,” Arthritis and Rheumatism, vol. 46, no. 1, pp. 114–123, 2002.
[115]
J. DeGroot, N. Verzijl, R. A. Bank, F. P. Lafeber, J. W. Bijlsma, and J. M. TeKoppele, “Age-related decrease in proteoglycan synthesis of human articular chondrocytes: the role of nonenzymatic glycation,” Arthritis and Rheumatism, vol. 42, no. 5, pp. 1003–1009, 1999.
[116]
J. DeGroot, N. Verzijl, M. Budde, J. W. J. Bijlsma, F. P. J. G. Lafeber, and J. M. TeKoppele, “Accumulation of advanced glycation end products decreases collagen turnover by bovine chondrocytes,” Experimental Cell Research, vol. 266, no. 2, pp. 303–310, 2001.
[117]
S. Fuchs, A. Skwara, M. Bloch, and B. Dankbar, “Differential induction and regulation of matrix metalloproteinases in osteoarthritic tissue and fluid synovial fibroblasts,” Osteoarthritis and Cartilage, vol. 12, no. 5, pp. 409–418, 2004.
[118]
M. A. Hofmann, S. Drury, B. I. Hudson et al., “RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response,” Genes and Immunity, vol. 3, no. 3, pp. 123–135, 2002.
[119]
D. L. Cecil, K. Johnson, J. Rediske, M. Lotz, A. M. Schmidt, and R. Terkeltaub, “Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products,” Journal of Immunology, vol. 175, no. 12, pp. 8296–8302, 2005.
[120]
A. Baillet, C. Trocmé, S. Berthier et al., “Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases,” Rheumatology, vol. 49, no. 4, pp. 671–682, 2010.
[121]
R. Kokkola, E. Sundberg, A.-K. Ulfgren et al., “High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis,” Arthritis and Rheumatism, vol. 46, no. 10, pp. 2598–2603, 2002.
[122]
J. R. Chen, M. Takahashi, M. Suzuki, K. Kushida, S. Miyamoto, and T. Inoue, “Pentosidine in synovial fluid in osteoarthritis and rheumatoid arthritis: relationship with disease activity in rheumatoid arthritis,” Journal of Rheumatology, vol. 25, no. 12, pp. 2440–2444, 1998.
[123]
D. Foell, D. Kane, B. Bresnihan et al., “Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis,” Rheumatology, vol. 42, no. 11, pp. 1383–1389, 2003.
[124]
R. Pullerits, I.-M. Jonsson, M. Verdrengh et al., “High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis,” Arthritis and Rheumatism, vol. 48, no. 6, pp. 1693–1700, 2003.
[125]
N. Taniguchi, K.-I. Kawahara, K. Yone et al., “High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine,” Arthritis and Rheumatism, vol. 48, no. 4, pp. 971–981, 2003.
[126]
M. M. C. Steenvoorden, R. E. M. Toes, H. K. Ronday, T. W. J. Huizinga, and J. DeGroot, “RAGE activation induces invasiveness of RA fibroblast-like synoviocytes in vitro,” Clinical and Experimental Rheumatology, vol. 25, no. 5, pp. 740–742, 2007.
[127]
T. K. Mukherjee, S. Mukhopadhyay, and J. R. Hoidal, “Implication of receptor for advanced glycation end product (RAGE) in pulmonary health and pathophysiology,” Respiratory Physiology and Neurobiology, vol. 162, no. 3, pp. 210–215, 2008.
[128]
G. R. Bernard, A. Artigas, K. L. Brigham et al., “The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination,” American Journal of Respiratory and Critical Care Medicine, vol. 149, no. 3, pp. 818–824, 1994.
[129]
R. Lucas, A. D. Verin, S. M. Black, and J. D. Catravas, “Regulators of endothelial and epithelial barrier integrity and function in acute lung injury,” Biochemical Pharmacology, vol. 77, no. 12, pp. 1763–1772, 2009.
[130]
X. Su, M. R. Looney, N. Gupta, and M. A. Matthay, “Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury,” The American Journal of Physiology, vol. 297, no. 1, pp. L1–L5, 2009.
[131]
P. R. Reynolds, R. E. Schmitt, S. D. Kasteler et al., “Receptors for advanced glycation end-products targeting protect against hyperoxia-induced lung injury in mice,” American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 5, pp. 545–551, 2010.
[132]
L. A. Parmley, N. D. Elkins, M. A. Fini, Y.-E. Liu, J. E. Repine, and R. M. Wright, “α-4/β-1 and α-L/β-2 integrins mediate cytokine induced lung leukocyte-epithelial adhesion and injury,” British Journal of Pharmacology, vol. 152, no. 6, pp. 915–929, 2007.
[133]
H. Zhang, S. Tasaka, Y. Shiraishi et al., “Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury,” American Journal of Respiratory and Critical Care Medicine, vol. 178, no. 4, pp. 356–362, 2008.
[134]
T. Uchida, M. Shirasawa, L. B. Ware et al., “Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury,” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 9, pp. 1008–1015, 2006.
[135]
C. S. Calfee, L. B. Ware, M. D. Eisner et al., “Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury,” Thorax, vol. 63, no. 12, pp. 1083–1089, 2008.
[136]
H. Wittkowski, A. Sturrock, M. A. D. Van Zoelen et al., “Neutrophil-derived S100A12 in acute lung injury and respiratory distress syndrome,” Critical Care Medicine, vol. 35, no. 5, pp. 1369–1375, 2007.
[137]
E. Abraham, J. Arcaroli, A. Carmody, H. Wang, and K. J. Tracey, “Cutting edge: HMG-1 as a mediator of acute lung inflammation,” Journal of Immunology, vol. 165, no. 6, pp. 2950–2954, 2000.
[138]
H. Ueno, T. Matsuda, S. Hashimoto et al., “Contributions of high mobility group box protein in experimental and clinical acute lung injury,” American Journal of Respiratory and Critical Care Medicine, vol. 170, no. 12, pp. 1310–1316, 2004.
[139]
J. Drazen, “Asthma,” in Cecil Textbook of Medicine, L. Goldman and D. Ausiello, Eds., pp. 502–508, W. B. Saunders, Philadelphia, Pa, USA, 22nd edition, 2004.
[140]
J. L. Simpson, S. Phipps, and P. G. Gibson, “Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis,” Pharmacology and Therapeutics, vol. 124, no. 1, pp. 86–95, 2009.
[141]
A. L. MacDowell and S. P. Peters, “Neutrophils in asthma,” Current Allergy and Asthma Reports, vol. 7, no. 6, pp. 464–468, 2007.
[142]
S. T. Holgate and R. Polosa, “The mechanisms, diagnosis, and management of severe asthma in adults,” The Lancet, vol. 368, no. 9537, pp. 780–793, 2006.
[143]
D. E. Shaw, M. A. Berry, B. Hargadon et al., “Association between neutrophilic airway inflammation and airflow limitation in adults with asthma,” Chest, vol. 132, no. 6, pp. 1871–1875, 2007.
[144]
T. Watanabe, K. Asai, H. Fujimoto, H. Tanaka, H. Kanazawa, and K. Hirata, “Increased levels of HMGB-1 and endogenous secretory RAGE in induced sputum from asthmatic patients,” Respiratory Medicine, vol. 105, no. 4, pp. 519–525, 2011.
[145]
Y. Zhou, Y. Q. Jiang, W. X. Wang et al., “HMGB1 and RAGE levels in induced sputum correlate with asthma severity and neutrophil percentage,” Human Immunology, vol. 73, no. 11, pp. 1171–1174, 2012.
[146]
M. B. Sukkar, L. G. Wood, M. Tooze et al., “Soluble RAGE is deficient in neutrophilic asthma and COPD,” European Respiratory Journal, vol. 39, no. 3, pp. 721–729, 2012.
[147]
P. S. Milutinovic, J. F. Alcorn, J. M. Englert, L. T. Crum, and T. D. Oury, “The receptor for advanced glycation end products is a central mediator of asthma pathogenesis,” The American Journal of Pathology, vol. 181, no. 4, pp. 1215–1225, 2012.
[148]
J. M. Englert, L. E. Hanford, N. Kaminski et al., “A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis,” The American Journal of Pathology, vol. 172, no. 3, pp. 583–591, 2008.
[149]
L. E. Hanford, C. L. Fattman, L. M. Schaefer, J. J. Enghild, Z. Valnickova, and T. D. Oury, “Regulation of receptor for advanced glycation end products during bleomycin-induced lung injury,” American Journal of Respiratory Cell and Molecular Biology, vol. 29, no. 3, pp. S77–S81, 2003.
[150]
L. Ramsgaard, J. M. Englert, C. L. Tobolewski, and T. D. Oury, “The role of RAGE in pulmonary silicosis,” American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 1, p. A740, 2008.
[151]
M. Kasper, D. Seidel, L. Knels et al., “Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl2 and TGF-β1,” Histochemistry and Cell Biology, vol. 121, no. 2, pp. 131–140, 2004.
[152]
E. Bargagli, F. Penza, N. Bianchi et al., “Controversial role of RAGE in the pathogenesis of idiopathic pulmonary fibrosis,” Respiratory Physiology and Neurobiology, vol. 165, no. 2-3, pp. 119–120, 2009.
[153]
M. He, H. Kubo, K. Ishizawa et al., “The role of the receptor for advanced glycation end-products in lung fibrosis,” The American Journal of Physiology, vol. 293, no. 6, pp. L1427–L1436, 2007.
[154]
P. Morbini, C. Villa, I. Campo, M. Zorzetto, S. Inghilleri, and M. Luisetti, “The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease?” Modern Pathology, vol. 19, no. 11, pp. 1437–1445, 2006.
[155]
M. M. Levy, M. P. Fink, J. C. Marshall et al., “2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference,” Critical Care Medicine, vol. 31, no. 4, pp. 1250–1256, 2003.
[156]
M. A. D. Van Zoelen, P.-F. Laterre, S. Q. Van Veen et al., “Systemic and local high mobility group box 1 concentrations during severe infection,” Critical Care Medicine, vol. 35, no. 12, pp. 2799–2804, 2007.
[157]
H. Wang, O. Bloom, M. Zhang et al., “HMG-1 as a late mediator of endotoxin lethality in mice,” Science, vol. 285, no. 5425, pp. 248–251, 1999.
[158]
M. A. Weigand, M. Volkmann, H. Schmidt, E. Martin, H. Bohrer, and H. J. Bardenheuer, “Neuron-specific enolase as a marker of fatal outcome in patients with severe sepsis or septic shock,” Anesthesiology, vol. 92, no. 3, pp. 905–907, 2000.
[159]
B. Liliensiek, M. A. Weigand, A. Bierhaus et al., “Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response,” Journal of Clinical Investigation, vol. 113, no. 11, pp. 1641–1650, 2004.
[160]
E. C. Lutterloh, S. M. Opal, D. D. Pittman et al., “Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection,” Critical Care, vol. 11, no. 6, article R122, 2007.
[161]
M. A. D. Van Zoelen, M. Schouten, A. F. de Vos et al., “The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia,” Journal of Immunology, vol. 182, no. 7, pp. 4349–4356, 2009.
[162]
F. Santilli, N. Vazzana, L. G. Bucciarelli, and G. Davì, “Soluble forms of RAGE in human diseases: clinical and therapeutical implications,” Current Medicinal Chemistry, vol. 16, no. 8, pp. 940–952, 2009.
[163]
S. S. Yan, Z.-Y. Wu, H. P. Zhang et al., “Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system,” Nature Medicine, vol. 9, no. 3, pp. 287–293, 2003.
[164]
Y. Chen, S. S. Yan, J. Colgan et al., “Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products,” Journal of Immunology, vol. 173, no. 2, pp. 1399–1405, 2004.
[165]
X. Chen, D. G. Walker, A. M. Schmidt, O. Arancio, L.-F. Lue, and S. D. Yan, “RAGE: a potential target for Aβ-mediated cellular perturbation in Alzheimer's disease,” Current Molecular Medicine, vol. 7, no. 8, pp. 735–742, 2007.
[166]
T. M. Wendt, N. Tanji, J. Guo et al., “RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy,” The American Journal of Pathology, vol. 162, no. 4, pp. 1123–1137, 2003.
