The etiology of sepsis: turned inside out

The sepsis syndrome is thought to occur when microbial products activate Toll-like receptors stimulating widespread inflammation, in turn causing organ failure, shock and death. However, recent discoveries reveal that: (i) not only microbial substances but also endogenous molecules can trigger Toll-like receptors; (ii) Toll-like receptor-4, the endotoxin receptor, is constitutively suppressed; and (iii) the first step in sepsis could be the release of Toll-like receptor-4 from suppression. These discoveries suggest that endotoxin might not always initiate the sepsis syndrome and they explain why anti-endotoxin therapies fail. The discoveries also suggest new therapeutic targets – endogenous agonists and Toll-like receptor regulators – for treatment of sepsis.