Various NOD-like receptors can sense intracellular pathogens or danger and assemble inflammasomes that activate the protease caspase-1 and leads to mature interleukin 1β (IL-1β) and IL-18 secretion. In Nature, Dixit and colleagues identify a role for mouse caspase-11 in response to cholera toxin B and infection by enteric bacteria. Casp11 is closely linked to Casp1 in the genome. Mouse strain 129 and 129-derived embryonic stem cells lack expression of caspase-11 due to a 5-base-pair deletion that disrupts exon splicing. Targeted Casp1−/− mice actually lack expression of both caspases, prompting a reassessment of their roles in IL-1β and IL-18 activation as well as induction of apoptosis. Although caspase-1 activation by ATP and uric acid remains intact, caspase-11 activation is mediated by a noncanonical inflammasome that does not require NLRP3 or ASC. Mice lacking caspase-11, but not caspase-1, alone survive lethal lipopolysaccharide challenge. It remains unknown what targets of caspase-11 mediate the tissue damage seen in septic shock; however, these findings suggest that caspase-1 is not the relevant executor. These results complicate interpretation of previous results implicating caspase-1 activity in sepsis.

Nature (16 October 2011) doi:10.1038/nature10558