No NLRP3 inflammasome activity in kidney epithelial cells, not even when the NLRP3-A350V Muckle-Wells variant is expressed in podocytes of diabetic mice

作者：Sophie Carina Kunte, Julian A. Marschner, Martin Klaus, Tamisa Seeko Bandeira Honda, Chenyu Li, Manga Motrapu, Christoph Walz, Maria Lucia Angelotti, Giulia Antonelli, Maria Elena Melica, Letizia De Chiara, Roberto Semeraro, Peter J. Nelson, Hans‐Joachim Anders · 发表于：Frontiers in Immunology · 年份：2023 · DOI：10.3389/fimmu.2023.1230050 · 被引用次数：11 · 研究领域：Inflammasome and immune disorders、Renal Diseases and Glomerulopathies、Dialysis and Renal Disease Management

Background The NLRP3 inflammasome integrates several danger signals into the activation of innate immunity and inflammation by secreting IL-1β and IL-18. Most published data relate to the NLRP3 inflammasome in immune cells, but some reports claim similar roles in parenchymal, namely epithelial, cells. For example, podocytes, epithelial cells critical for the maintenance of kidney filtration, have been reported to express NLRP3 and to release IL-β in diabetic kidney disease, contributing to filtration barrier dysfunction and kidney injury. We questioned this and hence performed independent verification experiments. Methods We studied the expression of inflammasome components in human and mouse kidneys and human podocytes using single-cell transcriptome analysis. Human podocytes were exposed to NLRP3 inflammasome agonists in vitro and we induced diabetes in mice with a podocyte-specific expression of the Muckle-Wells variant of NLRP3, leading to overactivation of the Nlrp3 inflammasome (Nphs2Cre;Nlrp3 A350V ) versus wildtype controls. Phenotype analysis included deep learning-based glomerular and podocyte morphometry, tissue clearing, and STED microscopy of the glomerular filtration barrier. The Nlrp3 inflammasome was blocked by feeding ß-hydroxy-butyrate. Results Single-cell transcriptome analysis did not support relevant NLRP3 expression in parenchymal cells of the kidney. The same applied to primary human podocytes in which NLRP3 agonists did not induce IL-1β or IL-18 secret...