Toll-Like Receptor 4 and Heat-Shock Protein 70: Is it a New Target Pathway for Diabetic Vasculopathies?

Author(s): Amanda Almeida de Oliveira, R. Clinton Webb, Kenia Pedrosa Nunes*.

Journal Name: Current Drug Targets

Volume 20 , Issue 1 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Diabetes is one of the most concerning diseases in modern times. Despite considerable advances in therapeutic management, the prevalence of diabetes and its contribution to death and disability continue to be a major health problem. Diabetic vasculopathies are the leading cause of mortality and morbidity in diabetic patients. Its pathophysiology includes oxidative stress, advanced glycation end products, and a low-grade inflammatory state. Lately, actions of the innate immune system via Toll-like receptors (TLRs) have been suggested as a new insight in this field. TLRs are pattern recognition receptors activated by highly conserved structural motifs of exogenous or endogenous ligands. Heat-shock proteins (HSPs), normally known for their ability to protect cells during stressful conditions, when released from injured cells bind to TLR4 and trigger the release of pro-inflammatory cytokines in a MyD88-dependent pathway. This pathway had been investigated in pancreatic beta cells and skeletal muscle, but it has not yet been explored in the vascular system and deserves investigation. In this work, the interplay between TLR4 and HSP70 in the vasculature during diabetes is reviewed and discussed. The current literature and preliminary results from our laboratory led us to hypothesize that hyperglycemia-associated HSP70 plays an important role in the pathophysiology of diabetic vasculopathies via the TLR4 pathway and might be a new target for therapeutic intervention.

Keywords: Hyperglycemia, toll-like receptor 4, heat-shock protein 70, pro-inflammatory cytokines, endothelial dysfunction, diabetic vasculopathies.

[1]
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442.
[2]
Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2008; 26(2): 77-82.
[3]
Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab 2016; 20(4): 546.
[4]
Nielsen TB, Pantapalangkoor P, Yan J, et al. Diabetes exacerbates infection via hyperinflammation by signaling through TLR4 and RAGE. MBio 2017; 8(4): e00818-17.
[5]
Szasz T, Wenceslau CF, Burgess B, Nunes KP, Webb RC. Toll-like receptor 4 activation contributes to diabetic bladder dysfunction in a murine model of type 1 diabetes. Diabetes 2016; 65(12): 3754-64.
[6]
Akira S, Bauer S, Hartmann G. Toll like receptors (TLRs) and innate immunity2008 Springer.
[7]
Nunes KP, Eric G, Theodora S, et al. The Innate immune system via toll-like receptors (TLRs) in Type 1 Diabetes-Mechanistic Insights.In Major Topics in Type 1 Diabetes2015 InTech.
[8]
Lu Y-C, Yeh W-C, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42(2): 145-51.
[9]
Lawrence T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 2009; 1(6): a001651.
[10]
Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS. Cutting edge: direct interaction of TLR4 with NAD (P) H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-κB. J Immunol 2004; 173(6): 3589-93.
[11]
Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 2003; 17(10): 1195-214.
[12]
Gregersen N, Bross P. Protein misfolding and cellular stress: an overview. Methods Mol Biol 2010; 3-23.
[13]
Szocs K. Endothelial dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrate tolerance. Gen Physiol Biophys 2004; 23: 265-96.
[14]
Schlesinger MJ, Ashburner M, Tissières A. Heat shock, from bacteria to man. Cold Spring Harbor Laboratory 1982.
[15]
Krause M, Rodrigues-Krause Jda C. Extracellular heat shock proteins (eHSP70) in exercise: possible targets outside the immune system and their role for neurodegenerative disorders treatment. Med Hypotheses 2011; 76(2): 286-90.
[16]
Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 1988; 52(2): 269-79.
[17]
Gay NJ, Keith FJ. Drosophila toll and IL-1 receptor. Nature 1991; 351: 355-6.
[18]
Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Sci 1998; 282(5396): 2085-8.
[19]
Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 2009; 22(2): 240-73.
[20]
Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4(7): 499-511.
[21]
Botos I, Segal DM, Davies DR. The structural biology of Toll-like receptors. Structure 2011; 19(4): 447-59.
[22]
Kaneto H, Katakami N, Matsuhisa M, Matsuoka TA. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm 2010; 2010: 453892.
[23]
Fakhruddin S, Alanazi W, Jackson KE. Diabetes-Induced reactive oxygen species: Mechanism of their generation and role in renal injury. J Diabetes Res 2017; 2017.
[24]
Sena CM, Pereira AM, Seiça R. Endothelial dysfunction-a major mediator of diabetic vascular disease. Biochim Biophys Acta 2013; 1832(12): 2216-31.
[25]
Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19(3): 257-67.
[26]
Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 2001; 276(20): 16683-9.
[27]
Weatherill AR, Lee JY, Zhao L, Lemay DG, Youn HS, Hwang DH. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4. J Immunol 2005; 174(9): 5390-7.
[28]
Boyle PJ. Diabetes mellitus and macrovascular disease: mechanisms and mediators. Am J Med 2007; 120(9): S12-7.
[29]
Marx N, Sukhova G, Murphy C, Libby P, Plutzky J. Macrophages in human atheroma contain PPARγ: differentiation-dependent peroxisomal proliferator-activated receptor γ (PPARγ) expression and reduction of MMP-9 activity through PPARγ activation in mononuclear phagocytes in vitro. Am J Pathol 1998; 153(1): 17-23.
[30]
Portik-Dobos V, Anstadt MP, Hutchinson J, Bannan M, Ergul A. Evidence for a matrix metalloproteinase induction/activation system in arterial vasculature and decreased synthesis and activity in diabetes. Diabetes 2002; 51(10): 3063-8.
[31]
Zhou H, Zhang X, Lu J. Progress on diabetic cerebrovascular diseases. Bosn J Basic Med Sci 2014; 14(4): 185.
[32]
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Invest 2006; 116(11): 3015.
[33]
Kim F, Pham M, Luttrell I, Bannerman DD, et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 2007; 100(11): 1589-96.
[34]
Devaraj S, Tobias P, Jialal I. Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes. Cytokine 2011; 55(3): 441-5.
[35]
Zhang H, Park Y, Wu J. Role of TNF-α in vascular dysfunction. Clin Sci 2009; 116(3): 219-30.
[36]
Mudaliar H. Pollock C1, Ma J, Wu H2, Chadban S, Panchapakesan U1. The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose. PLoS One 2014; 9(10): e108844.
[37]
Carrillo-Sepulveda MA, Spitler K, Pandey D, Berkowitz DE, Matsumoto T. Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats. J Mol Med 2015; 93(12): 1341-54.
[38]
Pahwa R, Nallasamy P, Jialal I. Toll-like receptors 2 and 4 mediate hyperglycemia induced macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx. J Diabetes Complications 2016; 30(4): 563-72.
[39]
Nunes KP, Bomfim GF, Toque HA, Szasz T, Clinton Webb R. Toll-like receptor 4 (TLR4) impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction. Life Sci 2017; 15(191): 219-26.
[40]
Nunes KP, de Oliveira AA, Szasz T, Biancardi VC, Webb RC. Blockade of toll-like receptor 4 attenuates erectile dysfunction in diabetic rats. J Sex Med 2018; 15(9): 1235-45.
[41]
Jee H. Size dependent classification of heat shock proteins: a mini-review. J Exerc Rehabil 2016; 12(4): 255.
[42]
Li Z, Srivastava P. Heat‐shock proteins Current Protocols in Immunology 2004; p A 1T 1-A 1T 6.
[43]
Matzinger P. An innate sense of danger. Semin Immunol 1998; 10(5): 399-415.
[44]
Asea A, Kabingu E, Stevenson MA, Calderwood SK. HSP70 peptide-bearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 2000; 5(5): 425-31.
[45]
Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001; 13(1): 114-9.
[46]
Asea A. Heat shock proteins and toll-like receptors.Toll-like receptors (TLRs) and innate immunity. Springer 2008; pp. pp. 111-127.
[47]
Asea A. Hsp70: a chaperokine. in Novartis Foundation symposium. 2008. Chichester; New York; John Wiley; 1999.
[48]
Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 2002; 277(17): 15107-12.
[49]
Krause MS, Oliveira LP Jr, Silveira EM, et al. MRP1/GS‐X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress‐induced redox imbalance in comparison to skeletal muscle cells? Cell biochemistry and function 2007; 25(1): 23-32.
[50]
Sajjadi AY, Mitra K, Grace M. Expression of heat shock proteins 70 and 47 in tissues following short-pulse laser irradiation: assessment of thermal damage and healing. Med Eng Phys 2013; 35(10): 1406-14.
[51]
Yang X-M, Baxter GF, Heads RJ, et al. Infarct limitation of the second window of protection in a conscious rabbit model. Cardiovasc Res 1996; 31(5): 777-83.
[52]
Beckmann RP, Lovett M, Welch WJ. Examining the function and regulation of hsp 70 in cells subjected to metabolic stress. J Cell Biol 1992; 117(6): 1137-50.
[53]
Tsan M-F, Gao B. Heat shock proteins and immune system. J Leukoc Biol 2009; 85(6): 905-10.
[54]
Gehrmann M, Marienhagen J, Eichholtz-Wirth H, et al. Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells. Cell Death Differ 2005; 12(1): 38.
[55]
Gomez-Pastor R, Burchfiel ET, Thiele DJ. Regulation of heat shock transcription factors and their roles in physiology and disease. Nature reviews. Mol Cell Biol 2018; 19(1): 4-19.
[56]
Åkerfelt M, Morimoto RI, Sistonen L. Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 2010; 11(8): 545.
[57]
Kim JY, Yenari MA. The immune modulating properties of the heat shock proteins after brain injury. Anat Cell Biol 2013; 46(1): 1-7.
[58]
Housby JN, Cahill CM, Chu B, et al. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 1999; 11(5): 347-58.
[59]
Asea A. Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 2005; 11: 34.
[60]
Chen L, Chen R, Wang H, et al. Mechanisms linking inflammation to insulin resistance Int J Endocrinol 2015 2015.
[61]
Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420(6913): 333.
[62]
Newsholme P, Haber EP, Hirabara SM, et al. Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J Physiol 2007; 583(Pt 1): 9-24.
[63]
Molina MN, Ferder L, Manucha W. Emerging role of nitric oxide and heat shock proteins in insulin resistance. Curr Hypertens Rep 2016; 18(1): 1.
[64]
Krause M, Heck TG, Bittencourt A, et al. The chaperone balance hypothesis: the importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management. Med Inflam 2015; 2015: 249205.
[65]
Rodrigues-Krause J, Krause M, O’Hagan C, et al. Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter? Cell Stress Chaperones 2012; 17(3): 293-302.
[66]
Karpe PA, Tikoo K. Heat shock prevents insulin resistance–induced vascular complications by augmenting angiotensin-(1-7) signaling. Diabetes 2014; 63(3): 1124-39.
[67]
Wu G, Meininger CJ. Nitric oxide and vascular insulin resistance. Biofactors 2009; 35(1): 21-7.
[68]
Krause M, Bock PM, Takahashi HK, et al. The regulatory roles of NADPH oxidase, intra-and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes. Clin Sci 2015; 128(11): 789-803.
[69]
Nakhjavani M, Morteza A, Khajeali L, et al. Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress Chaperones 2010; 15(6): 959-64.
[70]
Song J-m, Liu HX, Li Y, et al. Extracellular heat-shock protein 70 aggravates cerulein-induced pancreatitis through toll-like receptor-4 in mice. Chin Med J 2008; 121(15): 1420-5.
[71]
Vaz J, Akbarshahi H, Andersson R. Controversial role of toll-like receptors in acute pancreatitis. WJG 2013; 19(5): 616.
[72]
Reyna SM, Ghosh S, Tantiwong P, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 2008; 57(10): 2595-602.
[73]
González-Juanatey JR, Ezquerra EA, Barberác RG, et al. Disfunción eréctil como marcador de vasculopatía en la diabetes mellitus tipo 2 en España. Estudio DIVA. Med Clin 2009; 132(8): 291-7.
[74]
Isidro ML. Sexual dysfunction in men with type 2 diabetes. Postgrad Med J 2012; 88(1037): 152-9.
[75]
Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000; 163(2): 460-3.
[76]
Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84(1): 50-6.
[77]
Lindau ST, Gavrilova N. Sex, health, and years of sexually active life gained due to good health: evidence from two US population based cross sectional surveys of ageing. BMJ 2010; 340: c810.
[78]
Maiorino MI, Bellastella G, Esposito K. Diabetes and sexual dysfunction: current perspectives. Diabetes Metab Syndr Obes 2014; 7: 95-105.
[79]
Kloner R. Erectile dysfunction as a predictor of cardiovascular disease. Int J Impot Res 2008; 20(5): 460-5.
[80]
Baumhäkel M, Schlimmer N, Kratz MT, Böhm M, et al. Erectile dysfunction: indicator of end-organ damage in cardiovascular patients. Med Klin (Munich) 2009; 104(4): 309-13.
[81]
Garcia-Malpartida K, Mármol R, Jover A, et al. Relationship between erectile dysfunction and silent myocardial ischemia in type 2 diabetic patients with no known macrovascular complications. J Sex Med 2011; 8(9): 2606-16.
[82]
Montorsi P, Ravagnani PM, Galli S, et al. The artery size hypothesis: a macrovascular link between erectile dysfunction and coronary artery disease. Am J Cardiol 2005; 96(12): 19-23.
[83]
Nunes KP, Labazi H, Webb RC. New insights into hypertension-associated erectile dysfunction. Curr Opin Nephrol Hypertens 2012; 21(2): 163.
[84]
Musicki B, Hannan JL, Lagoda G, Bivalacqua TJ, Burnett AL. Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats. Androl 2016; 4(5): 977-83.
[85]
Furman BL. Streptozotocin‐induced diabetic models in mice and rats. Curr Protocols Pharmacol 2015; 5(47): 1-20.
[86]
Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70 role of Toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277(17): 15028-34.
[87]
Garamvölgyi Z, Prohászka Z, Rigó J Jr, Kecskeméti A, Molvarec A. Increased circulating heat shock protein 70 (HSPA1A) levels in gestational diabetes mellitus: a pilot study. Cell Stress Chaperones 2015; 20(4): 575-81.
[88]
Yabunaka N, Ohtsuka Y, Watanabe I, et al. Elevated levels of heat-shock protein 70 (HSP70) in the mononuclear cells of patients with non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1995; 30(2): 143-7.
[89]
Santos TMM, Sinzato YK, Gallego FQ, et al. Extracellular HSP70 levels in diabetic environment in rats. Cell Stress Chaperones 2015; 20(4): 595-603


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 1
Year: 2019
Page: [51 - 59]
Pages: 9
DOI: 10.2174/1389450119666180821105544
Price: $58

Article Metrics

PDF: 24
HTML: 4