Caspase-11 controls multiple pathways of inflammasome activation in response to bacterial secretion systems that access the host cytosol.

Three distinct inflammasome pathways are induced upon interaction of virulent bacteria with host cells. Translocation of flagellin into the host cytosol by specialized secretion systems triggers a NAIP5/NLRC4/caspase-1 inflammasome that leads to cell death, IL-1α, and IL-1β release. Virulent bacteria induce two separate pathways of caspase-11-dependent inflammasome activation through a two-signal model. First, TLR stimulation by PAMPs (signal one) leads to upregulation of pro-IL-1α, pro-IL-1β, NLRP3, and pro-caspase-11. Next, cytosolic detection of virulence activity, namely type III or type IV secretion (signal two), leads to caspase-11 processing and activation. Active caspase-11 contributes to NLRP3-mediated inflammasome activation and caspase-1-dependent IL-1β secretion. Caspase-11 also mediates caspase-1-independent cell death and IL-1α release through a pathway that is independent of the NLRP3/ASC and NAIP5/NLRC4 inflammasomes and involves an unknown host sensor.