Inflammasome components NLRP3/ASC in epithelial cells and resident dendritic cells of the kidney

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The NLRP3/ASC inflammasome is an intracellular signaling platform integrating multiple danger signals and activating local and systemic inflammation into proelolytic activation of IL-1beta and IL-18. During the last 10 years the functional importance of the NLRP3/ASC inflammasome has been well-documented for multiple acute and chronic disease states. We contributed to this effort by characterizing the roles of NLRP3 in kidney diseases. There is a broad consensus on ist role in dendritic cells and macrophages but NLRP3/ASC are also expressed by renal epithelial cell, i.e. podocytes and tubular cells. However, little is known on their functional roles there. Unpublished preliminary data support pro-fibrotic and anti-inflammatory effects of NLRP3/ASC, which shall be dissected in detail in this project. To do so, we will use transgeneic mice with selective de- or overactivation of NLRP3/ASC specifically in podocytes, tubular cells, and resident dendritic cells. First, we will characterize their spontaneous phenotypes and second, we will challenge them with metabolic and toxic stress to unravel their respective cell type-specific roles in kidney disease. These studies will characterize previously unknown or underrecognized functions of NLRP3/ASC and will help to better define and critically evaluate NLRP3/ASC as a potential therapeutic target.