FUNCTIONAL CHARACTERISTICS OF THE RAGE MOLECULE IN INTERCELLULAR INTERACTIONS IN NORMAL AND LUNG PATHOLOGY

DOI: https://doi.org/10.29296/24999490-2024-04-01

T.S. Zubareva(1, 3), K.O. Lykova(2), A.S. Panfilova(1, 3), P.R. Yablonsky(1) , T.V. Kvetnaia(3), M.A. Paltsev(4, 5)
1-St. Petersburg Research Institute of Phthisiopulmonology, Ministry of Health of the Russian Federation,
Ligovskiy Prospekt, 2–4, St. Petersburg, 191036, Russian Federation;
2-Federal State Autonomous Educational Institution of Higher Education “Peter the Great St. Petersburg Polytechnic University”,
st. Politekhnicheskaya, 29, St. Petersburg, 195251, Russian Federation;
3-ANO Scientific Research Center “St. Petersburg Institute of Bioregulation and Gerontology”,
Dynamo Ave., 3, St. Petersburg, 197110, Russian Federation;
4-Federal State Budgetary Educational Institution of Higher Education “Moscow State University named after M.V. Lomonosov”, Leninskie Gory, 1, Moscow, 119991, Russian Federation;
5-Federal State Autonomous Educational Institution of Higher Education
“Russian Peoples' Friendship University named after Patrice Lumumba”,
st. Miklouho-Maklaya, 6, Moscow, 117198, Russian Federation

Introduction. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that is highly expressed in healthy lungs and performs homeostatic function there. However, the exact mechanisms of development of these diseases remain unknown in most cases. Purpose of the study. Analysis of information about the role of RAGE and its signaling cascades in the pathogenesis of inflammatory, fibrotic and oncological lung diseases for a deeper understanding of signal modulation of this receptor. Material and methods. The review highlights the results of clinical and experimental studies obtained using methods for determining the quantitative expression of the receptor for advanced glycation end products (RAGE) and its ligands. When preparing materials, sources were used from international and domestic databases Scopus, Web of Science, Pub Medline, eLibrary, mainly over the past 15 years. Results. By binding the wide range of ligands, RAGE is directly involved in the inflammatory response to injury, fibrosis processes in the lungs and the occurrence of malignant neoplasms, thereby playing an important role in the development of many lung diseases. Conclusions. To obtain an informative picture of the pathogenesis of lung diseases, it is necessary to conduct a comprehensive assessment of the expression levels of both the RAGE signaling molecule itself and its isoforms and ligands.
Keywords: 
RAGE, sRAGE, AGEs, HMGB1, S100, NF-κB, inflammation, fibrosis, cancer
Список литературы: 
  1. Załęcki M., Korytko A., Zglejc-Waszak K., Szuszkiewicz J., Banach M. Role of RAGE in the Pathogenesis of Neurological Disorders. Neuroscience bulletin. 2022; 38 (10): 1248–62. DOI: 10.1007/s12264-022-00878-x.
  2. Neeper M., Schmidt A. M., Brett J., Yan S. D., Wang F., Pan Y. C., Elliston K., Stern D., Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J. of biological chemistry. 1992; 267 (21): 14998–5004. DOI: 10.1016/s0021-9258(18)42138-2.
  3. Oczypok E.A., Perkins T.N., Oury T.D. All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatric respiratory reviews. 2017; 23: 40–9. DOI: 10.1016/j.prrv.2017.03.012.
  4. Park H., Boyington, J.C. The 1.5 Å crystal structure of human receptor for advanced glycation endproducts (RAGE) ectodomains reveals unique features determining ligand binding. J. of Biological Chemistry. 2010; 285 (52): 40762–70. DOI: 10.1074/jbc.m110.169276.
  5. Ostendorp T., Leclerc E., Galichet A., Koch M., Demling N., Weigle B., Heizmann C. W., Kroneck P. M., Fritz G. Structural and functional insights into RAGE activation by multimeric S100B. The EMBO J. 2007; 26 (16): 3868–78. DOI: 10.1038/sj.emboj.7601805.
  6. Sessa L., Gatti E., Zeni F., Antonelli A., Catucci A., Koch M., Pompilio G., Fritz G., Raucci A., Bianchi M. E. The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). PloS one. 2014; 9 (1): e86903. DOI: 10.1371/journal.pone.0086903.
  7. Sharma A., Kaur S., Sarkar M., Sarin B. C., Changotra H. The AGE-RAGE Axis and RAGE Genetics in Chronic Obstructive Pulmonary Disease. Clinical Reviews in Allergy & Immunology. 2021; 60: 244–58. DOI: 10.1007/s12016-020-08815-4.
  8. Huttunen H.J., Kuja-Panula J., Rauvala H. Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J. of Biological Chemistry. 2002; 277 (41): 38635–46. DOI: 10.1074/jbc.M202515200.
  9. Brett J., Schmidt A.M., Yan S.D., Zou Y.S., Weidman E., Pinsky D., Nowygrod R., Neeper M., Przysiecki C., Shaw A., Migheli A., Stern D. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. The American J. of pathology. 1993; 143 (6): 1699–712. PMID: 8256857; PMCID: 1887265.
  10. Ott C., Jacobs K., Haucke E., Santos A. N., Grune T., Simm A. Role of advanced glycation end products in cellular signaling. Redox biology. 2014; 2: 411–29. DOI: 10.1016/j.redox.2013.12.016.
  11. Fehrenbach H., Kasper M., Tschernig T., Shearman M.S., Schuh D., Müller M. Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localization in rat and human lung. Cellular and molecular biology. 1998; 44 (7): 1147–57. PMID: 9846897.
  12. Dong H., Zhang Y., Huang Y., Deng H. Pathophysiology of RAGE in inflammatory diseases. Frontiers in Immunology. 2022; 13: 931473. DOI: 10.3389/fimmu.2022.931473.
  13. Liu J., Jin Z., Wang X., Jakoš T., Zhu J., Yuan Y. RAGE pathways play an important role in regulation of organ fibrosis. Life Sciences 2023, 121713. DOI: 10.1016/j.lfs.2023.121713.
  14. Muthyalaiah Y. S., Jonnalagadda B., John C. M., Arockiasamy S. Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconjugate J. 2021; 38 (6): 717–34. DOI: 10.1007/s10719-021-10031-x.
  15. Downs C.A., Johnson N.M., Tsaprailis G., Helms M.N. RAGE-induced changes in the proteome of alveolar epithelial cells. J. of proteomics. 2018; 177: 11–20. DOI: 10.1016/j.jprot.2018.02.010.
  16. Sukkar M.B., Ullah M.A., Gan W.J., Wark P.A., Chung K.F., Hughes J.M., Armour C.L., Phipps S. RAGE: a new frontier in chronic airways disease. British J. of pharmacology. 2012; 167 (6): 1161–76. DOI: 10.1111/j/1476-5381.2012.01984.x.
  17. Wolf L., Herr C., Niederstraßer J., Beisswenger C., Bals R. Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke. PLoS One. 2017; 12 (7). DOI: 10.1371/journal.pone.0180092.
  18. Machahua C., Montes-Worboys A., Llatjos R., Escobar I., Dorca J., Molina-Molina M., Vicens-Zygmunt V. Increased AGE-RAGE ratio in idiopathic pulmonary fibrosis. Respiratory Research. 2016; 17: 1–11. DOI: 10.1186/s12931-016-0460-2.
  19. Kierdorf K., Fritz G. RAGE regulation and signaling in inflammation and beyond. J. of leukocyte biology. 2013, 94 (1): 55–68. DOI: 10.1189/jlb.1012519.
  20. Lee H., Lee J., Hong S. H., Rahman I., Yang S. R. Inhibition of RAGE attenuates cigarette smoke-induced lung epithelial cell damage via RAGE-mediated Nrf2/DAMP signaling. Frontiers in Pharmacology. 2018; 9: 684. DOI: 10.3389/fphar.2018.00684.
  21. Vistoli G., De Maddis D., Cipak A., Zarkovic N., Carini M., Aldini G. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radical Research. 2013; 47: 3–27. DOI: 10.3109/10715762.2013.815348.
  22. Scaffidi P., Misteli T., Bianchi M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002; 418 (6894): 191–5. DOI: 10.1038/nature00858.
  23. Li G., Liang X., Lotze M. T. HMGB1: the central cytokine for all lymphoid cells. Frontiers in immunology. 2013; 4: 68. DOI: 10.3389/fimmu.2013.00068.
  24. Yamaguchi K., Iwamoto H., Sakamoto S., Horimasu Y., Masuda T., Miyamoto S., Nakashima T., Fujitaka K., Hamada H., Hattori N. Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation. Respiratory Investigation. 2022; 60 (4): 531–42.DOI: 10.1016/j.resinv.2022.04.004.
  25. Wu X., Mi Y., Yang H., Hu A., Zhang Q., Shang C. The activation of HMGB1 as progression factor on inflammation response in normal human bronchial epithelial cells through RAGE/JNK/NF-κB pathway. Molecular and cellular biochemistry. 2013; 380: 249–57. DOI: 10.1007/s11010-013-1680-0.
  26. Donato R., R. Cannon B., Sorci G., Riuzzi F., Hsu K., J. Weber D., L. Geczy C. Functions of S100 proteins. Current molecular medicine. 2013; 13 (1): 24–57. DOI: 10.2174/156652413804486214.
  27. Leclerc E., Fritz G., Vetter S. W., Heizmann C. W. Binding of S100 proteins to RAGE: an update. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2009; 1793 (6): 993–1007. DOI: 10.1016/j.bbamcr.2008.11.016.
  28. Kang J. H., Hwang S. M., Chung I. Y. S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC 5 AC via extracellular signal-regulated kinase and nuclear factor-κB pathways. Immunology. 2015; 144 (1): 79–90. DOI: 10.1111/imm.12352.
  29. Li J., Fei G. H. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease. Respiratory research. 2013; 14 (1): 1–9. DOI: 10.1186/1465-9921-14-140.
  30. Li J., Schmidt A.M. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J. of Biological Chemistry. 1997; 272 (26): 16498–506. DOI: 10.1074/jbc.272.26.16498.
  31. Hoonhorst S.J., Lo Tam Loi A. T., Pouwels S.D., Faiz A., Telenga E.D., van den Berge M., Koenderman L., Lammers J.W., Boezen H.M., van Oosterhout A.J., Lodewijk M.E., Timens W., Postma D.S., Ten Hacken N.H. Advanced glycation endproducts and their receptor in different body compartments in COPD. Respiratory research. 2016; 17: 1–12. DOI: 10.1186/s12931-016-0363-2.
  32. Nakamura T., Sato E., Fujiwara N., Kawagoe Y., Maeda S., Yamagishi S.I. Increased levels of soluble receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) are associated with death in patients with acute respiratory distress syndrome. Clinical biochemistry. 2011; 44 (8–9): 601–4. DOI: 10.1016/j.clinbiochem.2010.12.014.
  33. Jabaudon M., Blondonnet R., Roszyk L., Bouvier D., Audard J., Clairefond G., Fournier M., Marceau G., Déchelotte P., Pereira B., Sapin V., Constantin J.M. Soluble receptor for advanced glycation end-products predicts impaired alveolar fluid clearance in acute respiratory distress syndrome. American journal of respiratory and critical care medicine. 2015; 192 (2): 191–9. DOI: 10.1164/rccm.201501-0020OC.
  34. Downs C.A., Kreiner L.H., Johnson N.M., Brown L.A., Helms M.N. Receptor for advanced glycation end-products regulates lung fluid balance via protein kinase C–gp91phox signaling to epithelial sodium channels. American journal of respiratory cell and molecular biology. 2015; 52 (1): 75–87. DOI: 10.1165/rcmb.2014-0002OC.
  35. Chiappalupi S., Salvadori L., Donato R., Riuzzi F., Sorci G. Hyperactivated RAGE in comorbidities as a risk factor for severe COVID-19 – The role of RAGE-Ras crosstalk. Biomolecules. 2021; 11 (6): 876. DOI: 10.3390/biom11060876.
  36. Yalcin Kehribar D., Cihangiroglu M., Sehmen E., Avci B., Capraz A., Yildirim Bilgin A., Gunaydin C., Ozgen M. The Receptor for Advanced Glycation End Product (RAGE) Pathway in COVID-19, Biomarkers. 2021; 26 (2): 114–8. DOI: 10.1080/1354750X.2020.1861099.
  37. Machahua C., Montes-Worboys A., Planas-Cerezales L., Buendia-Flores R., Molina-Molina M., Vicens-Zygmunt V. Serum AGE/RAGEs as potential biomarker in idiopathic pulmonary fibrosis. Respiratory Research. 2018; 19 (1): 1–9. DOI: 10.1186/s12931-018-0924-7.
  38. Hara A., Sakamoto N., Ishimatsu Y., Kakugawa T., Nakashima S., Hara S., Adachi M., Fujita H., Mukae H., Kohno, S. S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis. Respiratory medicine. 2012; 106 (4): 571–80. DOI: 0.1016/j.rmed.2011.12.010.
  39. Yamaguchi K., Iwamoto H., Sakamoto S., Horimasu Y., Masuda T., Miyamoto S., Nakashima T., Ohshimo S., Fujitaka K., Hamada H., Hattori N. Serum high-mobility group box 1 is associated with the onset and severity of acute exacerbation of idiopathic pulmonary fibrosis. Respirology. 2020; 25 (3): 275–80. DOI: 10.1111/resp.13634.
  40. Lui G., Wong C.K., Ip M., Chu Y.J., Yung I.M., Cheung C.S., Zheng L., Lam J. S., Wong K.T., Sin W.W., Choi K.W., Lee N. HMGB1/RAGE signaling and pro-inflammatory cytokine responses in non-HIV adults with active pulmonary tuberculosis. PLoS One. 2016; 11 (7). DOI: 10.1371/journal.pone.0159132.
  41. Wu S., Mao L., Li Y., Yin Y., Yuan W., Chen Y., Ren W., Lu X., Li Y., Chen L., Chen B., Xu W., Tian T., Lu Y., Jiang L., Zhuang X., Chu M., Wu J. RAGE may act as a tumour suppressor to regulate lung cancer development. Gene. 2018; 651: 86–93. DOI: 10.1016/j.gene.2018.02.009.
  42. Ahmad S., Khan M. Y., Rafi Z., Khan H., Siddiqui Z., Rehman S., Shahab U., Khan M. S., Saeed M., Alouffi S., Khan M. S. Oxidation, glycation and glycoxidation – the vicious cycle and lung cancer. In Seminars in cancer biology. 2018; 49: 29–36. DOI: 10.1016/j.semcancer.2017.10.005.
  43. Ahmad S., Khan H., Siddiqui Z., Khan M. Y., Rehman S., Shahab U., Godovikova T., Silnikov V. AGEs, RAGEs and s-RAGE; friend or foe for cancer. In Seminars in cancer biology. 2018; 49: 44–55. DOI: 10.1016/j.semcancer.2017.07.001.
  44. Landskron G., De la Fuente M., Thuwajit P., Thuwajit C., Hermoso M. A. Chronic inflammation and cytokines in the tumor microenvironment. J. of immunology research. 2014. DOI: 10.1155/2014/149185.