Toll-like Receptor 2 Plays A Critical Role In Cardiac Dysfunction And High Mortality During Sepsis

Objectives:Sepsis is a systemic inflammatory response syndrome that occurs during infection and its induced mortality increased annually. To date, the pathophysiology of sepsis is considered to be the over activation of amounts of cytokine production and immune maladjustment. Toll-like receptors (TLRs) family are Pattern-recognition receptors (PRRs) initiate innate immunity through pathogen recognition, playing an important role in innate immunity, reflecting the first line of host defense against pathogen invasion. Recently, TLRs were demonstrated to be related to the development of cardiac disease. Strain rate (SR) imaging is a new developed technique which had been widely used to assess the ventricular contractility in cardiac resynchronization therapy patients. However little study about its use in detection of sepsis induced cardiac dysfunction in mouse model. Septic cardiomyopathy is a main feature of severe sepsis and contributes to its high mortality. Yet our understanding of the signaling mechanisms leading to septic cardiomyopathy is incomplete. The present study was to test the hypotheses that 1) Strain rate derived from Tissue Doppler Imaging can sensitively assess septic cardiac dysfunction in mouse model.2) Toll-like receptor 2 (TLR2) signaling is critical for cardiac dysfunction and high mortality in mice with severe polymicrobial sepsis.3) Complement factor B (cfB) is a critical downstream effector molecular of TLRs.Methods and Results:Cucem ligation and puncture (CLP) method was used to induce experimental polymicrobial sepsis in mice.24hours after CLP surgery, all mice were represented with cardiac dysfunction assessed by in vivo echocardiography---strain rate analysis, ex vivo isolated heart functional measurement and in vitro sarcomere shortening detection in adult mouse cardiomyocyte. Strain rate was identified as a sensitive method to evaluate CLP induced cardiac dysfunction. Compared to wild type (WT) mice subjected to sepsis, TLR2-/- mice had dramatically improved cardiac function after sepsis as demonstrated by in vivo serial echocardiography, better preserved left ventricular (LV) function in isolated heart, and improved sarcomere shortening in adult cardiomyocytes. There was also a significant survival benefit in TLR2-/-mice compared to WT mice. These favorable outcomes in TLR2-/-mice were associated with attenuated serum IL-6 and TNFa levels and enhanced neutrophil migratory function. The chimeric KO→WT mice, which completely lacked TLR2 gene expression by their bone marrow-derived hematopoietic cells but maintained normal TLR2 expression in the heart and other parenchymal tissues, were not protected from septic injury, exhibiting similar cytokine production, impairment of cardiac function, and mortality compared with the chimeric WT→WT control mice. Finally, the preliminary data suggest that complement factor B, a key component of alternative pathway, was significantly increase in the heart and in plasma in response to TLR2 activation and during polymicrobial sepsis.Conclusions:These studies suggest that:1) Strain rate was a sensitive and noninvasive method to assess CLP induced septic cardiomyopathy in mouse.2) TLR2 signaling, most likely that of the heart and other parenchymal tissues, plays a critical role in mediating cardiomyopathy, deleterious inflammation, and high mortality during polymicrobial sepsis. 3) cfB is likely a downstream effector of the TLR2-mediated cardiac dysfunction during polymicrobial sepsis.