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

NLRP3/ASC炎性小体是一个细胞内信号传导平台，整合多种危险信号，激活局部和全身性炎症，促进il -1 β和IL-18的前溶质活化。在过去的10年里，NLRP3/ASC炎性小体在多种急慢性疾病状态中的功能重要性已经得到了充分的证明。我们通过描述NLRP3在肾脏疾病中的作用为这一努力做出了贡献。NLRP3/ASC在树突状细胞和巨噬细胞中有广泛的作用，但NLRP3/ASC也在肾上皮细胞，即足细胞和小管细胞中表达。然而，人们对它们在那里的功能角色知之甚少。未发表的初步数据支持NLRP3/ASC的促纤维化和抗炎作用，本项目将对此进行详细分析。为此，我们将使用转基因小鼠，在足细胞、小管细胞和常驻树突状细胞中选择性地去激活或过度激活NLRP3/ASC。首先，我们将描述它们的自发表型，其次，我们将用代谢和毒性应激来挑战它们，以揭示它们在肾脏疾病中各自的细胞类型特异性作用。这些研究将描述NLRP3/ASC以前未知或未被充分认识的功能，并将有助于更好地定义和批判性地评估NLRP3/ASC作为潜在的治疗靶点。

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 Unpublished preliminary data support pro-fibrotic and anti-inflammatory effects of NLRP3/ASC, which shall be dissected in detail in this project.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.