Knockout of Toll-like receptor 4 improves survival and cardiac function in a murine model of severe sepsis

Abstract

Toll-like receptor 4 (TLR4) is a transmembrane pattern-recognition receptor expressed in immune cells and the heart. Activation of TLR4 signaling during sepsis results in the release of cardiac depression mediators that may impair heart function. The present-study aimed to determine whether TLR4 contributes to development of severe sepsis-induced myocardial dysfunction. A cecum ligation and puncture (CLP) procedure was employed to establish severe sepsis models. Wild type (WT) and TLR4 knock-out (TLR4-KO) mice were divided into four groups: WT-sham, TLR4-KO-sham, WT-CLP, and TLR4-KO-CLP. Cardiac function of these animals was evaluated at various time points following the surgical procedure. The expression levels of proinflammatory cytokines in the heart tissues were detected by reverse transcription-semi quantitative polymerase chain reaction (RT-PCR). Myocardial neutrophil and macrophage infiltration were investigated by histopathological examination, as well as a myeloperoxidase activity assay in heart tissue by RT-PCR. Myocardium Fas cell surface death receptor/Fas ligand and caspase-3 were also analyzed by RT-PCR. Additionally, myeloid differentiation primary response 88 M, toll or interleukin-1 receptor-domain-containing adapter-inducing interferon-β and nuclear factor-κB expression levels were observed in the myocardium of all four groups. WT-CLP mice exhibited increased mortality rates, more severe cardiac dysfunction and had increased levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α in heart tissues and increased neutrophil infiltration compared with TRL4-KO-CLP mice. The present-study reported that TLR4 aggravates severe sepsis-induced cardiac impairment by promoting the release of proinflammatory cytokines and neutrophil infiltration in hearts.