Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials

Significance: Sepsis is a critical clinical syndrome with life-threatening organ dysfunction induced by a dysregulated host response to infection. Despite decades of intensive research, sepsis remains a leading cause of in-hospital mortality with few specific treatments. Recent Advances: Toll-like receptors (TLRs) are a part of the innate immune system and play an important role in host defense against invading pathogens such as bacteria, virus, and fungi. Using a combination of genetically modified animal models and pharmacological agents, numerous preclinical studies during the past two decades have demonstrated that dysregulated TLR signaling may contribute to sepsis pathogenesis. However, many clinical trials targeting inflammation and innate immunity such as TLR4 have yielded mixed results. Critical Issues: Here we review various TLRs and the specific molecules these TLRs sense—both the pathogen-associated and host-derived stress molecules, and their converging signaling pathways. We critically analyze preclinical investigations into the role of TLRs in animal sepsis, the complexity of targeting TLRs for sepsis intervention, and the disappointing clinical trials of the TLR4 antagonist eritoran. Future Directions: Future sepsis treatments will depend on better understanding the complex biological mechanisms of sepsis pathogenesis, the high heterogeneity of septic humans as defined by clinical presentations and unique immunological biomarkers, and improved stratifications for targeted interventions.