Skip to main content

Advertisement

SpringerLink
Log in

Expatiating the molecular approaches of HMGB1 in diabetes mellitus: Highlighting signalling pathways via RAGE and TLRs

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Diabetes mellitus (DM) has become one of the major healthcare challenges worldwide in the recent times and inflammation being one of its key pathogenic process/mechanism affect several body parts including the peripheral and central nervous system. High-mobility group box 1 (HMGB1) is one of the major non-histone proteins that plays a key role in triggering the inflammatory response. Upon its release into the extracellular milieu, HMGB1 acts as an “alarmin” for the immune system to initiate tissue repair as a component of the host defense system. Furthermore, HMGB1 along with its downstream receptors like Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) serve as the suitable target for DM. The forthcoming research in the field of diabetes would potentially focus on the development of alternative approaches to target the centre of inflammation that is primarily mediated by HMGB1 to improve diabetic-related complications. This review covers the therapeutic actions of HMGB1 protein, which acts by activating the RAGE and TLR molecules to constitute a functional tripod system, in turn activating NF-κB pathway that contributes to the production of mediators for pro-inflammatory cytokines associated with DM. The interaction between TLR2 and TLR4 with ligands present in the host and the activation of RAGE stimulates various immune and metabolic responses that contribute to diabetes. This review emphasizes to elucidate the role of HMGB1 in the initiation and progression of DM and control over the inflammatory tripod as a promising therapeutic approach in the management of DM.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14:88–98. https://doi.org/10.1038/nrendo.2017.151

    Article  PubMed  Google Scholar 

  2. Wang Y, Zhong J, Zhang X et al (2016) The role of HMGB1 in the pathogenesis of type 2 diabetes. J Diabetes Res 2016:2543268. https://doi.org/10.1155/2016/2543268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu C, Feng X, Li Q, Wang Y et al (2016) Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: a systematic review and meta-analysis. Cytokine 86:100–109. https://doi.org/10.1016/j.cyto.2016.06.028

    Article  CAS  PubMed  Google Scholar 

  4. Wang X, Bao W, Liu J et al (2013) Inflammatory markers and risk of type 2 diabetes. Diabetes Care 36:166–175. https://doi.org/10.2337/dc12-0702

    Article  CAS  PubMed  Google Scholar 

  5. Massaro M, Scoditti E, Pellegrino M et al (2016) Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazarin attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes. Pharmacol Res 107:125–136. https://doi.org/10.1016/j.phrs.2016.02.027

    Article  CAS  PubMed  Google Scholar 

  6. Haraba R, Suica VI, Uyy E et al (2011) Antohe: Hyperlipidemia stimulates the extracellular release of the nuclear high mobility group box 1 protein. Cell Tissue Res 346:361–368. https://doi.org/10.1007/s00441-011-1277-4

    Article  CAS  PubMed  Google Scholar 

  7. Biscetti F, Ghirlanda G, Flex A (2011) Therapeutic potential of high mobility group box-1 in ischemic injury and tissue regeneration. Curr Vasc Pharmacol 9:677–681. https://doi.org/10.2174/157016111797484125

    Article  CAS  PubMed  Google Scholar 

  8. Tsung A, Tohme S, Billiar TR (2014) High-mobility group box-1 in sterile inflammation. J Intern Med 276:425–443. https://doi.org/10.2174/157016111797484125

    Article  CAS  PubMed  Google Scholar 

  9. Musumeci D, Roviello GN, Montesarchio D (2014) An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther 141:347–357. https://doi.org/10.1016/j.pharmthera.2013.11.001

    Article  CAS  PubMed  Google Scholar 

  10. Malarkey CS, Churchill M (2012) The high mobility group box: the ultimate utility player of a cell. Trends Biochem Sci 37:553–562. https://doi.org/10.1016/j.tibs.2012.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang L, Xie M, Yang M et al (2014) PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 5:4436. https://doi.org/10.1038/ncomms5436

    Article  CAS  PubMed  Google Scholar 

  12. Kang R, Zhang Q, Zeh HJ, Lotze MT, Tang D (2013) HMGB1 in cancer: good, bad, or both? Clin Cancer Res 19:4046–4057. https://doi.org/10.1158/1078-0432.CCR-13-0495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vijayakumar EC, Bhatt LK, Prabhavalkar KS (2019) High Mobility Group Box-1 (HMGB1): a potential target in therapeutics. Curr Drug Targets 20:1474–1485. https://doi.org/10.2174/1389450120666190618125100

    Article  CAS  PubMed  Google Scholar 

  14. Wu H, Chen Z, Xie J et al (2016) High Mobility Group Box-1: a missing link between diabetes and its complications. Mediat Inflamm 2016:3896147. https://doi.org/10.1155/2016/3896147

    Article  CAS  Google Scholar 

  15. Lugrin J, Rosenblatt-Velin N, Parapanov R, Liaudet L (2014) The role of oxidative stress during inflammatory processes. Biol Chem 395:203–230. https://doi.org/10.1515/hsz-2013-0241

    Article  CAS  PubMed  Google Scholar 

  16. Wang H, Qu H, Deng H (2015) Plasma HMGB-1 levels in subjects with obesity and type 2 diabetes: a cross-sectional study in China. PLoS One 10:e0136564. https://doi.org/10.1371/journal.pone.0136564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dasu MR, Devaraj S, Park S, Jialal I (2010) Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 33:861–868. https://doi.org/10.2337/dc09-1799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dandona P, Ghanim H, Green K, Sia CL et al (2013) Insulin infusion suppresses while glucose infusion induces toll-like receptors and high-mobility group-B1 protein expression in mononuclear cells of type 1 diabetes patients. Am J Physiol Endocrinol Metab 304:E810–E818. https://doi.org/10.1152/ajpendo.00566.2012

    Article  CAS  PubMed  Google Scholar 

  19. Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of toll-like receptor signalling complexes. Nat Rev Immunol 14:546. https://doi.org/10.1038/nri3713

    Article  CAS  PubMed  Google Scholar 

  20. Zhang S, Zhong J, Yang P, Gong F, Wang CY (2010) HMGB1, an innate alarmin, in the pathogenesis of type 1 diabetes. Int J Clin Exp Pathol 3:24–38. https://doi.org/10.7326/M20-0533

    Article  CAS  PubMed Central  Google Scholar 

  21. Wu H, Li R, Wei ZH, Zhang XL et al (2016) Diabetes-induced oxidative stress in endothelial progenitor cells may be sustained by a positive feedback loop involving high mobility group box-1. Oxidative Med Cell Longev 2016:1943918. https://doi.org/10.1155/2016/1943918

    Article  CAS  Google Scholar 

  22. Yang D, Tewary P, Rosa GDL, Wei F, Oppenheim JJ (2010) The alarmin functions of high-mobility group proteins. Biochim Biophys Acta 1799(1–2):157–163. https://doi.org/10.1016/j.bbagrm.2009.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tang D, Billiar TR, Lotze MT (2012) A Janus tale of two active High Mobility Group Box 1 (HMGB1) redox states. Mol Med 18:1360–1362. https://doi.org/10.2119/molmed.2012.00314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Venereau E, Casalgrandi M, Schiraldi M et al (2012) Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med 209:1519–1528. https://doi.org/10.1084/jem.20120189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (2013) RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 56:739–744. https://doi.org/10.1016/j.molimm.2013.07.008

    Article  CAS  PubMed  Google Scholar 

  26. Giovannini S, Tinelli G, Biscetti F et al (2017) Serum high mobility group box-1 and osteoprotegerin levels are associated with peripheral arterial disease and critical limb ischemia in type 2 diabetic subjects. Cardiovasc Diabetol 16:99. https://doi.org/10.1186/s12933-017-0581-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang S-L, Zhu L-Y, Han R et al (2017) Pathophysiology of peripheral arterial disease in diabetes mellitus. J Diabetes 9:133–140. https://doi.org/10.1111/1753-0407.12474

    Article  CAS  PubMed  Google Scholar 

  28. Nadeau-Vallée M, Obari D, Palacios J et al (2016) Sterile inflammation and pregnancy complications: a review. Reproduction 152:277–292. https://doi.org/10.1530/REP-16-0453

    Article  Google Scholar 

  29. Venereau E, Schiraldi M, Uguccioni M, Bianchi ME (2013) HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol 55:76–82. https://doi.org/10.1016/j.molimm.2012.10.037

    Article  CAS  PubMed  Google Scholar 

  30. Magna M, Pisetsky DS (2014) The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med 20:138–146. https://doi.org/10.2119/molmed.2013.00164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yanai H, Matsuda A, Koshiba R, Nishio J et al (2013) Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. PNAS 110:20699–20704. https://doi.org/10.1073/pnas.1320808110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Antoine DJ, Harris HE, Andersson U, Tracey KJ, Bianchi ME (2014) A systematic nomenclature for the redox states of high mobility group box (HMGB) proteins. Mol Med 20:135–137. https://doi.org/10.2119/molmed.2014.00022

    Article  PubMed  PubMed Central  Google Scholar 

  33. Schiraldi M, Raucci A, Munoz LM et al (2012) HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med 209:551–563. https://doi.org/10.1084/jem.20111739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Di Maggio S, Milan G, De Marchis F et al (2017) Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction. Biochim Biophys Acta 1863:2693–2704. https://doi.org/10.1016/j.bbadis.2017.07.012

    Article  CAS  Google Scholar 

  35. Vogel S, Rath D, Borst O et al (2016) Platelet-derived highmobility group box 1 promotes recruitment and suppresses apoptosis of monocytes. Biochem Biophys Res Commun 478:143–148. https://doi.org/10.1016/j.bbrc.2016.07.078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang H, Antoine DJ, Andersson U, Tracey KJ (2013) The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol 93:865–873. https://doi.org/10.1016/j.bbrc.2016.07.078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ma F, Kouzoukas DE, Meyer-Siegler KL et al (2017) Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4. BMC Physiol 17:6. https://doi.org/10.1186/s12899-017-0032-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kianian F, Kadkhodaee M, Sadeghipour HR, Karimian SM et al (2020) An overview of high-mobility group box 1, a potent pro-inflammatory cytokine in asthma. J Basic Clin Physiol Pharmacol 31(6):20190363. https://doi.org/10.1515/jbcpp-2019-0363

    Article  CAS  Google Scholar 

  39. Frank MG, Weber MD, Fonken LK et al (2016) The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: a role for the NLRP3 inflammasome. Brain Behav Immun 55:215–224. https://doi.org/10.1016/j.bbi.2015.10.009

    Article  CAS  PubMed  Google Scholar 

  40. Stark K, Philippi V, Stockhausen S et al (2016) Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 128:2435–2449. https://doi.org/10.1182/blood-2016-04-710632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang H, Lundback P, Ottosson L et al (2012) Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med 18:250–259. https://doi.org/10.2119/molmed.2011.00389

    Article  CAS  PubMed  Google Scholar 

  42. Singh B, Biswas I, Bhagat S, Surya Kumari S, Khan GA (2016) HMGB1 facilitates hypoxia-induced WF upregulation through TLR2MYD88-SP1 pathway. Eur J Immunol 46:2388–2400. https://doi.org/10.1002/eji.201646386

    Article  CAS  PubMed  Google Scholar 

  43. Yao H, Hu C, Yin L et al (2016) Dioscin reduces lipopolysaccharide-induced inflammatory liver injury via regulating TLR4/MyD88 signal pathway. Int Immunopharmacol 36:132–141. https://doi.org/10.1016/j.intimp.2016.04.023

    Article  CAS  PubMed  Google Scholar 

  44. Arrigo T, Chirico V, Salpietro V et al (2013) High-mobility group protein B1: a new biomarker of metabolic syndrome in obese children. Eur J Endocrinol 168(4):631–638

    Article  CAS  PubMed  Google Scholar 

  45. Montes VN, Subramanian S, Goodspeed L et al (2015) Anti-HMGB1 antibody reduces weight gain in mice fed a high-fat diet. Nutr Diabetes 5:e161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sumiyoshi M, Satomi J, Kitazato KT, Yagi K et al (2015) PPARγ dependent and -independent inhibition of the HMGB1/TLR9 pathway by eicosapentaenoic acid attenuates ischemic brain damage in ovariectomized rats. J Stroke Cerebrovasc Dis 24:1187–1195. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.009

    Article  PubMed  Google Scholar 

  47. Song F, Del Pozo CH, Rosario R et al (2014) RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice. Diabetes 63(6):1948–1965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Xie HL, Zhang Y, Huang YZ, Li S et al (2014) Regulation of high mobility group box 1 and hypoxia in the migration of mesenchymal stem cells. Cell Biol Int 38:892–897. https://doi.org/10.1002/cbin.10279

    Article  CAS  PubMed  Google Scholar 

  49. Yu M, Wang H, Ding A et al (2006) HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26:174–179. https://doi.org/10.1189/jlb.0306180

    Article  CAS  PubMed  Google Scholar 

  50. Kang R, Livesey KM, Zeh HJ, Loze MT, Tang D (2010) HMGB1: a novel beclin 1-binding protein active in autophagy. Autophagy 6:1209–1211. https://doi.org/10.4161/auto.6.8.13651

    Article  CAS  PubMed  Google Scholar 

  51. Kim S, Kim SY, Pribis JP et al (2013) Signaling of high mobility group box 1 (HMGB1) through toll-like receptor 4 in macrophages requires CD14. Mol Med 19:88–98. https://doi.org/10.2119/molmed.2012.00306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yamashita A, Nishihira K, Matsuura Y et al (2012) Paucity of CD34-positive cells and increased expression of high-mobility group box 1 in coronary thrombus with type 2 diabetes mellitus. Atherosclerosis 224:511–514. https://doi.org/10.1016/j.atherosclerosis.2012.07.027

    Article  CAS  PubMed  Google Scholar 

  53. Syed MA, Barinas-Mitchell E, Pietropaolo SL et al (2002) Is type 2 diabetes a chronic inflammatory/autoimmune disease? Diabetes Nutr Metab 15:68–83. https://doi.org/10.1242/dmm.036004

    Article  CAS  PubMed  Google Scholar 

  54. Matsuoka N, Itoh T, Watari H et al (2010) High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice. J Clin Invest 120:735–743. https://doi.org/10.1172/JCI41360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang H, Hreggvidsdottir HS, Palmblad K et al (2010) A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA 107:11942–11947. https://doi.org/10.1073/pnas.1003893107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yamamoto M, Takeda K (2010) Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract 2010:240365. https://doi.org/10.1155/2010/240365

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ruan BH, Li X, Winkler AR et al (2010) Complement C3a, CpG oligos, and DNA/C3a complex stimulate IFN-alpha production in a receptor for advanced glycation end product-dependent manner. J Immunol 185:4213–4222. https://doi.org/10.4049/jimmunol.1000863

    Article  CAS  PubMed  Google Scholar 

  58. Yamamoto Y, Harashima A, Saito H et al (2011) Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol 186:3248–3257. https://doi.org/10.4049/jimmunol.1002253

    Article  CAS  PubMed  Google Scholar 

  59. Bierhaus A, Nawroth PP (2009) 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 52:2251–2263. https://doi.org/10.1007/s00125-009-1458-9

    Article  CAS  PubMed  Google Scholar 

  60. Wang CY, Podolsky R, She JX (2006) Genetic and functional evidence supporting SUMO4 as a type 1 diabetes susceptibility gene. Ann N Y Acad Sci 1079:257–267. https://doi.org/10.1196/annals.1375.039

    Article  CAS  PubMed  Google Scholar 

  61. Yang H, Wang H, Czura CJ, Tracey KJ (2005) The cytokine activity of HMGB1. J Leukoc Biol 78(1):1–8

    Article  CAS  PubMed  Google Scholar 

  62. Pietropaolo M, Barinas-Mitchell E, Kuller LH (2007) The heterogeneity of diabetes: unraveling a dispute: is systemic inflammation related to islet autoimmunity? Diabetes 56:1189–1197. https://doi.org/10.2337/db06-0880

    Article  CAS  PubMed  Google Scholar 

  63. Kazama H, Ricci JE, Herndon JM et al (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of highmobility group box-1 protein. Immunity 29:21–32. https://doi.org/10.1016/j.immuni.2008.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dumitriu IE, Bianchi ME, Bacci M, Manfredi AA, Rovere-Querini P (2007) The secretion of HMGB1 is required for the migration of maturing dendritic cells. J Leukoc Biol 81:84–91. https://doi.org/10.1189/jlb.0306171

    Article  CAS  PubMed  Google Scholar 

  65. Telusma G, Datta S, Mihajlov I et al (2006) Dendritic cell activating peptides induce distinct cytokine profiles. Int Immunol 18:1563–1573

    Article  CAS  PubMed  Google Scholar 

  66. Yang D, Chen Q, Yang H et al (2007) High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol 81:59–66. https://doi.org/10.1189/jlb.0306180

    Article  CAS  PubMed  Google Scholar 

  67. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D et al (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290:C917–C924. https://doi.org/10.1152/ajpcell.00401.2005

    Article  CAS  PubMed  Google Scholar 

  68. Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13:460–469. https://doi.org/10.1016/j.molmed.2007.09.002

    Article  CAS  PubMed  Google Scholar 

  69. Ivanov S, Dragoi AM, Wang X et al (2007) A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 110:1970–1981. https://doi.org/10.1182/blood-2006-09-044776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Han J, Zhong J, Wei W, Wang Y et al (2008) Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice. Diabetes 57:2118–2127. https://doi.org/10.2337/db07-1499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. O’Brien BA, Geng X, Orteu GH et al (2006) A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse. J Autoimmun 26:104–115. https://doi.org/10.1016/j.jaut.2005.11.006

    Article  CAS  PubMed  Google Scholar 

  72. Moser B, Szabolcs MJ, Ankersmit HJ et al (2007) Blockade of RAGE suppresses alloimmune reactions in vitro and delays allograft rejection in murine heart transplantation. Am J Transplant 7:293–302. https://doi.org/10.1111/j.1600-6143.2006.01617.x

    Article  CAS  PubMed  Google Scholar 

  73. Yi S, Wang Y, Chandra AP et al (2007) Requirement of MyD88 for macrophage-mediated islet xenograft rejection after adoptive transfer. Transplantation 83:615–623. https://doi.org/10.1097/01.tp.0000253759.87886.39

    Article  CAS  PubMed  Google Scholar 

  74. Goldberg A, Parolini M, Chin BY et al (2007) Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J 21:2840–2848. https://doi.org/10.1096/fj.06-7910com

    Article  CAS  PubMed  Google Scholar 

  75. Chen Y, Akirav EM, Chen W et al (2008) RAGE ligation affects T cell activation and controls T cell differentiation. J Immunol 181:4272–4278. https://doi.org/10.4049/jimmunol.181.6.4272

    Article  CAS  PubMed  Google Scholar 

  76. Inoue K, Kawahara K, Biswas KK et al (2007) Hmgb1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques. Cardiovasc Pathol 1(6):136–143. https://doi.org/10.1016/j.carpath.2006.11.006

    Article  CAS  Google Scholar 

  77. Penfold SA, Coughlan MT, Patel SK et al (2010) Circulating high-molecular-weight rage ligands activate pathways implicated in the development of diabetic nephropathy. Kidney Int 7(8):287–295. https://doi.org/10.1038/ki.2010.134

    Article  CAS  Google Scholar 

  78. Sohn EJ, Kim CS, Kim YS et al (2007) Effects of magnolol (5,5 diallyl-2,2′-dihydroxybiphenyl) on diabetic nephropathy in type 2 diabetic Goto-Kakizaki rats. Life Sci 80:468–475. https://doi.org/10.1016/j.lfs.2006.09.037

    Article  CAS  PubMed  Google Scholar 

  79. Abdelsadik A, Trad A (2011) Toll-like receptors on the fork roads between innate and adaptive immunity. Hum Immunol 72:1188–1193. https://doi.org/10.1016/j.humimm.2011.08.015

    Article  CAS  PubMed  Google Scholar 

  80. Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444(7121):840–846

    Article  CAS  PubMed  Google Scholar 

  81. Clynes R, Moser B, Yan SF et al (2007) Receptor for age (RAGE): weaving tangled webs within the inflammatory response. Curr Mol Med 7:743–751. https://doi.org/10.2174/156652407783220714

    Article  CAS  PubMed  Google Scholar 

  82. Thornalley PJ (2007) Dietary ages and ales and risk to human health by their interaction with the receptor for advanced glycation end products (RAGE) – an introduction. Mol Nutr Food Res 5(1):1107–1110. https://doi.org/10.1002/mnfr.200700017

    Article  CAS  Google Scholar 

  83. Ramasamy R, Yan SF, Schmidt AM (2007) Arguing for the motion: yes, RAGE is a receptor for advanced glycation end products. Mol Nutr Food Res 5(1):1111–1115. https://doi.org/10.1002/mnfr.200700008

    Article  CAS  Google Scholar 

  84. Heizmann CW (2007) The mechanism by which dietary ages are a risk to human health is via their interaction with rage: arguing against the motion. Mol Nutr Food Res 5(1):1116–1119. https://doi.org/10.1002/mnfr.200600284

    Article  CAS  Google Scholar 

  85. Foell D, Wittkowski H, Vogl T, Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 8(1):28–37. https://doi.org/10.1189/jlb.0306170

    Article  CAS  Google Scholar 

  86. Yuan M, Konstantopoulos N, Lee J et al (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293(5535):1673–1677

    Article  CAS  PubMed  Google Scholar 

  87. Zheng L, Sinniah R, Hsu SI (2008) Pathogenic role of NF-kappaB activation in tubulointerstitial inflammatory lesions in human lupus nephritis. J Histochem Cytochem 5(6):517–529 10.1369%2Fjhc.7A7368.2008

    Article  Google Scholar 

  88. Göser S, Andrassy M, Buss SJ et al (2006) Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation 114(16):1693–1702. https://doi.org/10.1161/CIRCULATIONAHA.106.635664

    Article  CAS  PubMed  Google Scholar 

  89. Chen Y, Qiao F, Zhao Y, Wang Y, Liu G (2015) HMGB1 is activated in type 2 diabetes mellitus patients and in mesangial cells in response to high glucose. Int J Clin Exp Pathol 8(6):6683–6691

    PubMed  PubMed Central  Google Scholar 

  90. Böni-Schnetzler M, Boller S, Debray S et al (2009) Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150(12):5218–5229

    Article  PubMed  Google Scholar 

  91. Dumitriu IE, Baruah P, Valentinis B et al (2005) Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol 174(12):7506–7515. https://doi.org/10.4049/jimmunol.174.12.7506

    Article  CAS  PubMed  Google Scholar 

  92. Jaulmes A, Thierry S, Janvier B, Raymondjean M (2006) Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta. FASEB J 20(10):1727–1729. https://doi.org/10.1096/fj.05-5514fje

    Article  CAS  PubMed  Google Scholar 

  93. Mitola S, Belleri M, Urbinati C et al (2006) Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol 176(1):12–15. https://doi.org/10.4049/jimmunol.176.1.12

    Article  CAS  PubMed  Google Scholar 

  94. Harja E, Bu DX, Hudson BI et al (2008) Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE−/− mice. J Clin Invest 118(1):183–194. https://doi.org/10.1172/JCI32703

    Article  CAS  PubMed  Google Scholar 

  95. Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150(6):1223–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hudson BI, Kalea AZ, Del Mar A et al (2008) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283:34457–34468. https://doi.org/10.1016/j.cclet.2018.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ramasamy R, Yan SF, Schmidt AM (2009) RAGE: therapeutic target and biomarker of the inflammatory response-the evidence mounts. J Leukoc Biol 86:505–512. https://doi.org/10.1189/jlb.0409230

    Article  CAS  PubMed  Google Scholar 

  98. Nativel B et al (2013) Soluble HMGB1 is a novel adipokine stimulating IL-6 secretion through RAGE receptor in SW872 preadipocyte cell line: contribution to chronic inflammation in fat tissue. PLoS One 8(9):e76039. https://doi.org/10.1371/journal.pone.0076039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Soro-Paavonen A, Watson AMD, Li J et al (2008) Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 57:2461–2469. https://doi.org/10.2337/db07-1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Volz HC, Seidel C, Laohachewin D, Kaya Z et al (2010) HMGB1: the missing link between diabetes mellitus and heart failure. Basic Res Cardiol 105:805–820. https://doi.org/10.1007/s00395-010-0114-3

    Article  CAS  PubMed  Google Scholar 

  101. Wang WK, Lu QH, Zhang JN et al (2014) HMGB1mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1signalling pathway. J Cell Mol Med 18:2311–2320. https://doi.org/10.1111/jcmm.12399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tao A, Song J, Lan T, Xu X et al (2015) Cardiomyocyte-fibroblast interaction contributes to diabetic cardiomyopathy in mice: Role of HMGB1/TLR4/IL-33 axis. Biochim Biophys Acta 1852:2075–2085. https://doi.org/10.1016/j.bbadis.2015.07.015

    Article  CAS  PubMed  Google Scholar 

  103. Jiang S, Chen X (2017) HMGB1 siRNA can reduce damage to retinal cells induced by high glucose in vitro and in vivo. Drug Des Devel Ther 11:783–795. https://doi.org/10.2147/DDDT.S129913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang W, Wang Y, Kong Y (2019) Exosomes derived from mesenchymal stem cells modulate miR-126 to ameliorate hyperglycemia-induced retinal inflammation via targeting HMGB1. Investig Ophthalmol Vis Sci 60:294–303. https://doi.org/10.1167/iovs.18-25617

    Article  CAS  Google Scholar 

  105. Liu L, Patel P, Steinle JJ (2018) PKA regulates HMGB1 through activation of IGFBP-3 and SIRT1 in human retinal endothelial cells cultured in high glucose. Inflamm Res Off J Eur Histamine Res Soc 67:1013–1019. https://doi.org/10.1007/s00011-018-1196-x

    Article  CAS  Google Scholar 

  106. Raucci A, Di Maggio S, Scavello F et al (2019) The Janus face of HMGB1 in heart disease: a necessary update. Cell Mol Life Sci 76:211–229. https://doi.org/10.1007/s00018-018-2930-9

    Article  CAS  PubMed  Google Scholar 

  107. Wang W-K, Wang B, Lu Q-H, Zhang W et al (2014) Inhibition of high-mobility group box 1 improves myocardial fibrosis and dysfunction in diabetic cardiomyopathy. Int J Cardiol 172:202–212. https://doi.org/10.1016/j.ijcard.2014.01.011

    Article  PubMed  Google Scholar 

  108. Heng LZ, Comyn O, Peto T et al (2013) Diabetic retinopathy: Pathogenesis, clinical grading, management and future developments. Diabet Med J Br Diabet Assoc 30:640–650. https://doi.org/10.1111/dme.12089

    Article  CAS  Google Scholar 

  109. Hu J, Liu B, Zhao Q, Jin P et al (2016) Bone marrow stromal cells inhibits HMGB1-mediated inflammation after stroke in type 2 diabetic rats. Neuroscience 324:11–19. https://doi.org/10.1016/j.neuroscience.2016.02.058

    Article  CAS  PubMed  Google Scholar 

  110. Coughlan MT, Thorburn DR, Penfold SA et al (2009) RAGE induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol 20:742–752. https://doi.org/10.1681/ASN.2008050514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

    Tapan Behl, Eshita Sharma, Aayush Sehgal, Ishnoor Kaur, Arun Kumar, Rashmi Arora & Munish Kakkar

  2. Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India

    Giridhari Pal

  3. Cardiovascular Research Institute, Icahn School of Medicine, New York, USA

    Ravinder Kumar

  4. Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania

    Simona Bungau

Authors
  1. Tapan Behl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eshita Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aayush Sehgal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ishnoor Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arun Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rashmi Arora
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giridhari Pal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Munish Kakkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ravinder Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Simona Bungau
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TB: Conceived the idea, Wrote the article; ES and AS: Review of Literature; IK: Revision and Editing; RA: Drafting and alignment; GP and MK: Figure Work; RK and SB: Proof Read.

Corresponding author

Correspondence to Tapan Behl.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Behl, T., Sharma, E., Sehgal, A. et al. Expatiating the molecular approaches of HMGB1 in diabetes mellitus: Highlighting signalling pathways via RAGE and TLRs. Mol Biol Rep 48, 1869–1881 (2021). https://doi.org/10.1007/s11033-020-06130-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-06130-x

Keywords

Search

Navigation