Abstract
BackgroundSepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis.MethodsWe assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages.ResultsTherapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)–dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis.ConclusionsThese novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients.
Highlights
Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis
Flagellin protected against abdominal sepsis via Toll-like receptor 5 (TLR5) To determine whether flagellin was sufficient to improve mortality in lethal sepsis, we examined the effects of flagellin administration using a mouse model of cecal ligation and puncture (CLP)-induced lethal sepsis
In line with an increased mortality rate, control mice presented with lethargy and piloerection as soon as 24 h after CLP, which are clinical signs of severe sepsis (Fig. 1c), and we studied bacterial loads in peritoneal lavage fluids (PLF), spleen, and blood after 24 h of CLP showing markedly reduced bacterial numbers in flagellin-treated animals (Fig. 1d)
Summary
Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis. Sepsis progresses when the initial host response fails to control the infection, resulting in widespread inflammation and multiple organ injury [3]. In a post-mortem study of 235 patients in surgical intensive care who were admitted with sepsis, about 80% of patients had unresolved septic foci at death [5]. Toll-like receptors (TLRs) are central for host defense against pathogenic microorganisms by recognizing conserved motifs in pathogens termed pathogen-associated molecular patterns [6]. TLR5 is the receptor for extracellular flagellin, which is a component of motile bacteria [7]. Animal data have demonstrated that TLR5 agonist flagellin restored antibiotic-impaired innate immune defenses and restricted colonization with vancomycin-resistant Enterococcus (VRE) [9]. Whether TLR5 plays a role in controlling infection during sepsis has yet to be addressed.
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