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

AJBM  Volume 2, Issue 1, pages 80–93, January 2014

Rong Zhang, Steven Singh, Xiang Ha, George Cowsik, Oleg Lavezzi, Hiroshi Caudell, Roschelle Ohura

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

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