Inner sensors of endotoxin - implications for sepsis research and therapy

Despite great efforts and numerous clinical trials, there is still a major need for effective therapies for sepsis. Neutralization or elimination of bacterial toxins remains a promising approach. The understanding of the interaction of the endotoxin (lipopolysaccharide, LPS) of Gram-negative bacteria with its cellular receptor, namely the CD14/TLR4/MD2 complex, was a major breakthrough. Unfortunately, clinical trials for sepsis on the neutralization of LPS or on the inhibition of TLR4 signaling failed whereas those on LPS removal remain controversial. Recent discoveries of another class of LPS receptors localized within the cytoplasm, namely caspase-11 in mice and caspases-4/5 in humans, have renewed interest in the field. These provide new potential targets for intervention in sepsis pathogenesis. Since cytoplasmic recognition of LPS induces non-canonical inflammasome pathway, a potentially harmful host response, it is conceivable to therapeutically target this mechanism. However, a great deal of care should be used in the translation of research on the non-canonical inflammasome inhibition due to multiple inter-species differences. In this review, we summarize the knowledge on endotoxin sensing in sepsis with special focus on the intracellular sensing. We also highlight the murine versus human differences and discuss potential therapeutic approaches addressing the newly discovered pathways.