Final Report Summary - FLAMMASEC (Inflammasome-induced IL-1 Secretion: Route, Mechanism, and Cell Fate) Inflammation is a complex response to infection, irritants or tissue damage that protects our body from infections and promotes healing, but can also cause disease when not properly controlled. Cytokines are proteins secreted by immune cells that can promote inflammation. Most cytokines are secreted from the cell via successive transport through the endoplasmic reticulum, the Golgi apparatus, and secretory vesicles. In contrast, cytokines of the interleukin (IL)-1 family are produced in an inactive form in the cytoplasm and are secreted by a poorly understood mechanism called unconventional protein secretion. The bioactivation of IL-1 and its secretion are controlled by the protease caspase-1, which is part of a protein complex called the inflammasome. Caspases are proteases that have essential roles in cell death. While several other caspases control an immunologically silent form of cell death called apoptosis, caspase-1 activation at inflammasomes triggers a distinct, inflammatory form of cell death called pyroptosis. The goal of this ERC-funded project was to investigate how caspase-1 controls secretion of IL-1 and pyroptosis. We have generated an experimental system that allows genetic dissection of protease activity-dependent and -independent activities of caspase-1. Our results provided important mechanistic insight into how caspase-1 controls IL-1 secretion and cell fate decisions after inflammasome activation. We found that the protease activity of caspase-1 is essential for these effects. We identified gasdermin D as a target of caspase-1 protease activity upon inflammasome activation in primary immune cells and confirmed that this pore-forming protein mediates both IL-1 release and pyroptosis. Furthermore, our investigations show that delayed but robust fail-safe mechanisms engaged in the absence of caspase-1 protease activity allow for non-canonical maturation and secretion of IL-1. The inflammasome is critical for defence against infections, but is also a known instigator of inflammatory diseases such as particle-induced sterile inflammation (as is seen in gout and asbestosis), hereditary periodic fever syndromes, and metabolic diseases like diabetes and atherosclerosis, as well as neurological diseases such as multiple sclerosis, Alzheimer's disease and Parkinson’s disease. Our results suggest that inhibiting the protease activity of caspase-1 is a potential avenue for therapeutic intervention. Industry is developing such drugs and the tools we developed within this project are used to evaluate the efficacy of candidate drug compounds.
