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.


METHODS
Controlled animal study.


METHODS
University research laboratory.


METHODS
Male C57BL/6, wild-type, Toll-like receptor 3-/-.


METHODS
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.


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-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.


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.
Department of Surgery, Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
Ming
M
Gao
Tuanzhu
T
Ha
Xia
X
Zhang
Li
L
Liu
Xiaohui
X
Wang
Jim
J
Kelley
Krishna
K
Singh
Race
R
Kao
Xiang
X
Gao
David
D
Williams
Chuanfu
C
Li
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D004452:Echocardiography; D024202:Electrophoretic Mobility Shift Assay; D006321:Heart / Q000503:physiopathology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis / Q000382:microbiology / Q000503:physiopathology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*
C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D009195:Peroxidase