TLR3 exaggerated sepsis induced cardiac dysfunction via activation of TLR4-mediated NF-κB and TRIF/IRF signaling pathways


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Rong Zhang 1, Steven Singh, Xiang Ha, George Cowsik, Oleg Lavezzi, Hiroshi Caudell, Roschelle Ohura*
Author Affiliations
∗Correspondence author e-mail: roschelleo1@yahoo.com: 1University of Mississippi Medical Center in Jackson, MS 38677, United States

 

Abstract

Cardiovascular dysfunction is a major consequence of septic shock and contributes to the high morbidity and mortality of sepsis. Groups of proteins that comprise the Toll or Toll-like family of receptors detect the pathogen and mount a rapid defensive response in vertebrate and invertebrate organisms, through induction of innate immune and inflammatory responses. The engagement of TLR4 homodimers by LPS or other protein cognate the ligands initiates a signaling cascade and thus induces genes involved in the immune response against pathogens. TLRs have been implicated in cardiac dysfunction in several important disease states, including ischemia/reperfusion (I/R) injury. MyD88 contains an N-terminal death domain and a C-terminal TIR domain. When stimulated, MyD88 is recruited and, in the early phase, interacts with the cytoplasmic TIR domain of TLR4. Although TLR3 is known to respond to RNA from damage cells, the importance of this response in vivo during acute inflammatory processes has not been fully understood. Our result shows that TLR3−/− rat significantly attenuated myocardial NF-κB binding activity both the levels of phosphorylated IκBα/IκBα after LPS administration, and improved cardiac function and reduce the inflammatory response. Further, LPS increased levels of TLR4, TRIF and IFN-β in the myocardium. Interestingly the TLR4-activation signaling was significantly prevented by TLR3 deficiency. We concluded that the use of antibody directed against TLR3 might serve as a therapeutic clinical option in the treatment of cardiac dysfunction induced by sepsis.

Key words: TLR3; TLR4; TRIF; IFN-β; LPS; Cardiac dysfunction

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

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  1. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013;13(12):862–74.
  2. Rudiger A, Singer M. The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol 2013;11(2):187–95.
  3. Tavener SA, Kubes P. Is there a role for cardiomyocyte toll-like receptor 4 in endotoxemia? Trends Cardiovasc Med 2005;15(5):153–7.
  4. Hedayat M, Netea MG, Rezaei N. Targeting of toll-like receptors: a decade of progress in combating infectious diseases. Lancet Infect Dis 2011;11(9):702–12.
  5. Al-Amran FG, Yousif NG, Meng XM. A TLR4-MCP-1-macrophage IL-18 cascade plays a major role in myocardial injury and cardiac dysfunction after permanent ischemia. Journal of Surgical Research 2011;165(2):258.
  6. Gao M, Ha T, Zhang X, Wang X, et al. The toll-like receptor 9 ligand, CpG oligodeoxynucleotide, attenuates cardiac dysfunction in polymicrobial sepsis, involving activation of both phosphoinositide 3 kinase/Akt and extracellular-signal-related kinase signaling. J Infect Dis 2013;207(9):1471–9.
  7. Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 2011;187(5):2626–31.
  8. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 2000;87(3):241–7.
  9. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–787.
  10. Ao L, Li J, Aly A, E Austin, DA Fullerton, X Meng. Myocardial tissue TLR4 plays a major role in mediating myocardial injury following cold ischemia and reperfusion through up-regulation of MCP-1. Journal of Surgical Research 2011;165 (2):181.
  11. Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2007;4:444–454.
  12. Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008;205:2609–2621.
  13. Williams DL, Li C, Ha T, et al. Modulation of the phosphoinositide 3-Kinase pathway alters innate resistance to polymicrobial sepsis. J Immunol. 2004;172:449–456.
  14. Cavaillon J-M, Adib-Conquy M. Monocytes/macrophages and sepsis. Crit Care Med. 2005;33:S506–S509.
  15. Sun R, Zhang Y, Lv Q, et al. Toll-like receptor 3 (TLR3) induces apoptosis via death receptors and mitochondria by up-regulating the transactivating p63 isoform {alpha} (tap63{alpha}) J Biol Chem. 2011;286:15918–15928.
  16. Yousif NG, Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC cardiovascular disorders 20111;11(1):62.
  17. inck BW, Tsen MF, Islas M, et al. Bone marrow-derived cells contribute to contractile dysfunction in endotoxic shock. Am J Physiol Heart Circ Physiol. 2005;288:577–583.
  18. Yang YL, Wang Y, Shyu J, Zhang N. Critical role of NQO1 in ovarian cell injury: highly risk of ovarian carcinoma. Journal of cellular cancer 2013;1:1-9.
  19. Ogiku L, Fujii R, Xiao S, Xuehao L. Meloxicam attenuates brain cell injury following cerebral ischemia and reperfusion via down regulation of proinflammatory response. Journal of cellular cancer 2013;2(1):1-11.
  20. Raeburn CD, Calkins CM, et al. Vascular cell adhesion molecule-1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction. Surgery 2001;130(2):319–25.
  21. Sharshar T, Gray F, Lorin de la Grandmaison G, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 2003;362(9398):1799–805.
  22. Oberholzer A, Oberholzer C, Moldawer LL. Sepsis Syndromes: Understanding the Role of Innate and Acquired Immunity. Shock. 2001;16:83–96.
  23. Ha T, Hu Y, Liu L, et al. TLR2 ligands induce cardioprotection against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Cardiovascular Research. 2010;87:694–703.
  24. Cao Z, Hu Y, Wu W, et al. The TIR/BB-loop mimetic AS-1 protects the myocardium from ischaemia/reperfusion injury. Cardiovascular Research. 2009;84:442–451.
  25. Sun R, Zhang Y, Lv Q, et al. Toll-like receptor 3 (TLR3) induces apoptosis via death receptors and mitochondria by up-regulating the transactivating p63 isoform {alpha} (tap63{alpha}) J Biol Chem. 2011;286:15918–15928.
  26. Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H. Role of toll-like receptors in the development of sepsis. Shock. 2008;29(3):315–21.
  27. Zhang C. The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol. 2008;103(5):398–406.
  28. Lundberg AM, Drexler SK, et al. Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. Blood. 2007;110(9):3245–52.
  29. Borbiev T, Birukova A, Liu F, et al. p38 MAP kinase-dependent regulation of endothelial cell permeability. Am J Physiol Lung Cell Mol Physiol. 2004;287(5):L911–8.
  30. Yamashita T, Kawashima S, Ohashi Y, et al. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation. 2000;101(8):931–7.
  31. Di Lorenzo A, Lin MI, Murata T, et al. eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and rho GTPases. J Cell Sci. 2013;126(Pt 24:5541–52.
  32. Tanoue T, Adachi M, Moriguchi T, Nishida E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2000;2(2):110–6.

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Review Article
DOI: http://dx.doi.org/10.18081/2333-5106/014-01/125-136
American Journal of BioMedicine 2014, Volume 2, Issue 2, pages 125-136
Received 23 January 2014; accepted 24 May 2014; Published June 26, 2014

How to cite this article
Zhang R, Singh S, Ha X, et al. TLR3 exaggerated sepsis induced cardiac dysfunction via activation of TLR4-mediated NF-κB and TRIF/IRF signaling pathways. American Journal of BioMedicine 2014;2(2):125-136.

Case report outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

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