We determined the roles of TLR3 and TLR9 in adverse events of polymicrobial
sepsis, with a focus on development of septic
cardiomyopathy, progression of which we have recently shown to be
complement- and
histones-dependent. So Wt, TLR3-knocked out (K.O.), and TLR9-K.O. mice were subjected to polymicrobial
sepsis following cecal
ligation and
puncture (CLP). In the absence of either TLR3 or TLR9, the intensity of echocardiogram (Echo)-Doppler dysfunction during development of
cardiomyopathy was substantially reduced in the K.O. mice. Based on our prior studies emphasizing the adverse effects of plasma C5a and
histones in the
cardiomyopathy of
sepsis, in TLR3- and TLR9-K.O. mice, there were striking reductions in plasma levels of C5a and
histones as well as reduced levels of
cytokines in plasma and heart tissue after CLP. Since we know that
histones cause cardiac dysfunction, rat cardiomyocytes (CMs) were exposed in vitro to the
histones (purified from calf thymus), which caused
bleb formation on the surfaces of CMs, suggesting
histones may perturb the cell membrane of CMs. In vitro, exposure of CMs to the
histones for 3 hours caused
lactate dehydrogenase release from CMs. These data indicate that
sepsis-induced cardiac dysfunction requires presence of TLR3 and TLR9 and may be linked to
histone-induced damage of CMs.