The healthy gastro-intestinal tract is home to trillions of microbes living in peaceful harmony with the mucosal immune system. Maintenance of this intestinal immune homeostasis is regulated by a cross talk between the gut microbiota, mucosal immune cells and intestinal epithelial cells, three factors that are influenced by the host ‘inflammasomes’. The latter are a set of multi-protein complexes that upon activation of their central caspase component mediate pro-inflammatory cytokine maturation and sometimes also induce cell death. While all inflammasomes until very recently were thought to be centred around caspase-1, brand new evidence has now revealed the existence of caspase-11-dependent inflammasomes. However, nothing is currently known about the respective roles of caspase-1 and -11 in colitis and intestinal inflammation. To remedy this situation, this project’s central aim is to delineate and to understand the differential contributions of caspase-1- and caspase-11-dependent inflammasomes in the maintenance of intestinal immune homeostasis. For achieving this goal, we will evaluate the responses of conditionally targeted cell type-specific caspase-1 and -11 knockout mice in three different models of intestinal inflammation that recapitulate aspects of the environmental, genetic and infectious factors underlying intestinal disease development in humans. In addition to characterising the roles of the respective inflammasome types as well as the cell types in which they act, we will elucidate the intracellular, immunological and ‘gut ecological’ mechanisms by which caspase-1 and caspase-11 differentially modulate host susceptibility to intestinal inflammation. By establishing the mechanisms and cell types through which inflammasomes modulate intestinal host-microbe communication, this work will markedly advance our understanding of how inflammasome signalling determines intestinal disease
susceptibility, and may reveal novel opportunities for preventing and treating inflammatory bowel disease in humans.