Major focus of AG Wree is the exploration of cellular and molecular mechanisms in inflammatory liver diseases. A special focus is on the contribution of the NLRP3 inflammasome in acute and chronic liver injury. The NLRP3 inflammasome is a multi-protein cytoplasmic complex that serves as pattern recognition receptor and has emerged as key mediator of inflammation, immunity, and cell death.
Mechanisms of NLRP3 inflammasome activation. Inflammasome components such as NLRP3, NLRP1, ASC and caspase 1 are expressed in Kupffer cells and hepatocytes. Inflammasome activation is dependent on two successive signals. Signal 1 (dotted lines), driven by TLR and IL 1R signalling, includes expression of component proteins including NLRP3, ASC and pro-caspase 1 and pro-IL 1β and pro-IL 18.117 Signal 2 is provided by PAMPs and/or DAMPs leading to oligomerization of the inflammasome components and cleavage of caspase 1, which ultimately leads to release of active proinflammatory cytokines. IL 1Ra inhibits downstream effects of IL 1, as well as blocking the IL 1-driven autoinflammatory loop. Abbreviations: DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; TLR, Toll-like receptor. (From Wree et al. Nat Rev Gastroenterol Hepatol. 2013)