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

Objective: To determine the role of Toll-like receptor 3 in cardiac dysfunction during polymicrobial sepsis. Design: Controlled animal study. Setting: University research laboratory. Subjects: Male C57BL/6, wild-type, Toll-like receptor 3(-/-). Intervention: 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. Measurements and Main Results: 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-kappa B and Toll/IL-1 receptor-domain-containing adapter-inducing interferon-beta-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. Conclusions: 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. (Crit Care Med 2012; 40:2390-2399)