Final Report Summary - INFLAMMACT (Role of caspase-11 in inflammasome signaling and the innate immune response)
In this project, we addressed this issue by monitoring cytokine defects in caspase-11 deficient mice and cells in mouse and cellular models of infection and inflammation. In aim 1 of the project, we set up a colony of caspase-11-deficient mice in our facility, macrophages of which are used to study the role of caspase-11 in inflammasome activation and IL-1beta secretion. We found that caspase-11 is dispensable for inflammasome activation and cytokine secretion from LPS-activated macrophages exposed to canonical inflammasome triggers such as ATP, Salmonella and dsDNA. However, caspase-11 was required for inflammasome activation and IL-1beta secretion in response to enterobacteria such as E. coli and C. rodentium. Caspase-11 was also required for IL-1beta secretion during LPS-induced endotoxemia in vivo. In aim 2 of the project, we determined the proteome-wide digestome of caspase-11. Putative caspase-11 substrates identified by this analysis have been validated in in vitro setups with recombinantly purified caspase-11, in overexpression systems and a subset was confirmed in cellular and in vivo models of inflammation and infection. Ongoing studies are aimed at further validating the role of these caspase-11 substrates in cellular and in vivo models of inflammation and infection. Full elucidation of the role of caspase-11 in inflammasome signaling and the innate immune response will provide new insights into the mechanisms governing immunity and may pave the way for new therapeutic approaches for autoimmune disorders.