Human caspase-4 and caspase-5 assemble into non-canonical inflammasomes in response to overlapping and distinct LPS structures

In response to bacterial lipopolysaccharide (LPS) exposure, human caspase-4 (CASP4) and caspase-5 (CASP5) assemble into non-canonical inflammasomes called supramolecular organizing centers (SMOCs), according to recent research. Like mouse caspase-11 (Casp11), caspases-4 and -5 form SMOCs in a catalytically dependent manner when activated by LPS.

While CASP11 oligomerizes in response to cytosolic LPS, CASP4 and CASP5 exhibit differential responses to distinct LPS structural variants. These variations fail to activate CASP11 but induce SMOC formation when activating LPS structures are present. Importantly, transgenic mice expressing CASP4 instead of Casp11 show more effective control of Francisella novicida, a rodent pathogen whose LPS evades detection by TLR4 and Casp11.

However, mice expressing CASP4 are more susceptible to sepsis when exposed to E. coli that carries a lipid A variant which fails to activate TLR4 and Casp11. These findings suggest that human CASP4 and CASP5 have evolved to respond to a wider range of LPS structures compared to mouse Casp11. The study highlights a potential tradeoff between systemic inflammation and bacterial infection control, which may explain the observed differences between human and mouse innate immune responses.

The findings may help inform the development of targeted therapeutic strategies for gram-negative bacterial infections and sepsis, ultimately benefiting human health.