Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis

• Published in: Critical care medicine Vol. 40; no. 8; p. 2390
• Main Authors: Gao, Ming, Ha, Tuanzhu, Zhang, Xia, Liu, Li, Wang, Xiaohui, Kelley, Jim, Singh, Krishna, Kao, Race, Gao, Xiang, Williams, David, Li, Chuanfu
• Format: Journal Article
• Language: English
• Published: United States 01.08.2012
• Subjects: Animals; Apoptosis - physiology; Blotting, Western; Echocardiography; Electrophoretic Mobility Shift Assay; Heart - physiopathology; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Neutrophils - physiology; Peroxidase - metabolism; Sepsis - microbiology; Sepsis - physiopathology; Toll-Like Receptor 3 - physiology
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0b013e3182535aeb

To determine the role of Toll-like receptor 3 in cardiac dysfunction during polymicrobial sepsis. Controlled animal study. University research laboratory. Male C57BL/6, wild-type, Toll-like receptor 3-/-. Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. Toll-like receptors (TLRs) play a critical role in the pathophysiology of sepsis/septic shock. TLR3 is located in intracellular endosomes, and recognizes double-stranded RNA. This study examined the role of TLR3 in cardiac dysfunction following cecal ligation and puncture (CLP)-induced sepsis. TLR3 knockout (TLR3-/-, n=12) and age-matched wild-type (n=12) mice were subjected to CLP. Cardiac function was measured by echocardiography before and 6 hrs after CLP. CLP resulted in significant cardiac dysfunction as evidenced by decreased ejection fraction by 25.7% and fractional shortening by 29.8%, respectively. However, TLR3-/- mice showed a maintenance of cardiac function at pre-CLP levels. Wild-type mice showed 50% mortality at 58 hrs and 100% mortality at 154 hrs after CLP. In striking contrast, 70% of TLR3-/- mice survived indefinitely, that is, >200 hrs. TLR3 deficiency significantly decreased CLP-induced cardiac-myocyte apoptosis and attenuated CLP-induced Fas and Fas ligand expression in the myocardium. CLP-activation of TLR4-mediated nuclear factor-κB and Toll/IL-1 receptor-domain-containing adapter-inducing interferon-β-dependant interferon signaling pathways was prevented by TLR3 deficiency. In addition, CLP-increased vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression, and neutrophil and macrophage sequestration in the myocardium were also attenuated in septic TLR3-/- mice. More significantly, adoptive transfer of wild-type bone-marrow stromal cells to TLR3-/- mice abolished the cardioprotective effect in sepsis. These data indicate that TLR3 plays a deleterious role in mediating cardiac dysfunction in sepsis. Thus, modulation of the TLR3 activity may be useful in preventing cardiac dysfunction in sepsis.