Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity

•Murine caspase-11 senses Gram-negative bacterial infection and triggers pyroptosis.•Cytoplasmic LPS is the agonist of the caspase-11 pathway.•Caspase-11 and human caspase-4/caspase-5 are activated by direct LPS binding.•Caspase sensing of cytosolic LPS mediates endotoxic shock independently of TLR4.

Lipopolysaccharide (LPS) is the major component of Gram-negative bacteria cell wall. In innate immunity, extracellular LPS is recognized by Toll-like receptor 4 to stimulate cytokine transcription. Recent studies suggest a ‘non-canonical inflammasome’ that senses cytoplasmic LPS and activates caspase-11 in mouse macrophages. Unexpectedly, biochemical studies reveal that caspase-11 and its human orthologs caspase-4/caspase-5 are LPS receptors themselves. Direct LPS binding induces caspase-4/caspase-5/caspase-11 oligomerization and activation, triggering cell pyroptosis and anti-bacterial defenses. Caspase-4/caspase-5/caspase-11 recognition of intracellular LPS requires bacterial escape from the vacuole; this process is promoted by interferon-inducible GTPases-mediated lysis of the bacteria-containing vacuole. Non-canonical activation of these inflammatory caspases by LPS not only represents a new paradigm in innate immunity but also critically determines LPS-induced septic shock in mice.