Cytosolic Sensor of Bacterial Lipopolysaccharide in Human Macrophages

Endotoxin - bacterial lipopolysaccharide (LPS) - is a driver of the lethal infection sepsis through activation of innate immune responses. When delivered to the cytosol of macrophages, LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has been doubted by many investigators, as caspases-4, -5, and -11 bind and activate LPS directly in vitro. Here we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS required for efficient activation of the caspase-4 inflammasome in human macrophages. NLRP11 is present in humans and other primates, but absent in mice, likely explaining why it has been missed in screens looking for innate immune signaling molecules, most of which have been carried out in mice. NLRP11 is a previously missing link and a component of the human caspase-4 inflammasome activation pathway. One Sentence SummaryDiscovery that human macrophages contain a cytosolic receptor for bacterial lipopolysaccharide.