Skip to main content
European Commission logo print header

Role of caspase-11 in inflammasome signaling and the innate immune response

Final Report Summary - INFLAMMACT (Role of caspase-11 in inflammasome signaling and the innate immune response)

Microbial infections and autoimmune diseases continue to threaten human health worldwide. Orchestration of an appropriate host defence responses against bacterial and viral infections is accomplished in part through the production of potent inflammatory cytokines. In particular, the related cytokines interleukin (IL)-1beta and IL-18 were recognized early on for their ability to cause a wide variety of biological effects associated with infection, inflammation and autoimmune processes. These cytokines are matured in large protein complexes termed inflammasomes through proteolytic maturation by the cystein protease caspase-1. Unlike caspase-1, the roles of the closely related cystein protease caspase-11 in cytokine maturation remain unclear.

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.