Journal Article

Crucial Role of NLRP3 Inflammasome in the Development of Peritoneal Dialysis-related Peritoneal Fibrosis

Karasawa, Tadayoshi, Kamata, Ryo, Takahashi, Masafumi, Kasahara, Tadashi, Komada, Takanori, Kimura, Hiroaki, Nagata, Daisuke, Aizawa, Emi, Morishita, Yoshiyuki, Watanabe, Sachiko, Ito, Homare, Hishida, Erika, Akimoto, Tetsu

2019

Overview

Long-term peritoneal dialysis (PD) therapy leads to peritoneal inflammation and fibrosis. However, the mechanism underlying PD-related peritoneal inflammation and fibrosis remains unclear. NLRP3 inflammasome regulates the caspase-1-dependent release of interleukin-1β and mediates inflammation in various diseases. Here, we investigated the role of NLRP3 inflammasome in a murine model of PD-related peritoneal fibrosis induced by methylglyoxal (MGO). Inflammasome-related proteins were upregulated in the peritoneum of MGO-treated mice. MGO induced parietal and visceral peritoneal fibrosis in wild-type mice, which was significantly reduced in mice deficient in NLRP3, ASC, and interleukin-1β (IL-1β). ASC deficiency reduced the expression of inflammatory cytokines and fibrotic factors, and the infiltration of macrophages. However, myeloid cell-specific ASC deficiency failed to inhibit MGO-induced peritoneal fibrosis. MGO caused hemorrhagic ascites, fibrin deposition, and plasminogen activator inhibitor-1 upregulation, but all of these manifestations were inhibited by ASC deficiency. Furthermore, in vitro experiments showed that MGO induced cell death via the generation of reactive oxygen species in vascular endothelial cells, which was inhibited by ASC deficiency. Our results showed that endothelial NLRP3 inflammasome contributes to PD-related peritoneal inflammation and fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/21 / 13/51 / 38/77 / 631/443/272 / 64 / 64/60 / 692/4022/1950/1724 / Animal models / Animals / Ascites / CARD Signaling Adaptor Proteins - deficiency / CARD Signaling Adaptor Proteins - genetics / CARD Signaling Adaptor Proteins - physiology / Caspase / Caspase-1 / Cell death / Cytokines / Dialysis / Disease Models, Animal / Endothelial cells / Endothelial Cells - metabolism / Endothelial Cells - pathology / Female / Fibrin / Fibrosis / Hemorrhage / Human Umbilical Vein Endothelial Cells / Humanities and Social Sciences / Humans / IL-1β / Inflammasomes / Inflammasomes - physiology / Inflammation / Interleukin-1beta - deficiency / Interleukin-1beta - genetics / Interleukin-1beta - physiology / Leukocytes - pathology / Macrophages / Macrophages - pathology / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / NLR Family, Pyrin Domain-Containing 3 Protein - deficiency / NLR Family, Pyrin Domain-Containing 3 Protein - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - physiology / Peritoneal dialysis / Peritoneal Dialysis - adverse effects / Peritoneal Fibrosis - chemically induced / Peritoneal Fibrosis - etiology / Peritoneal Fibrosis - pathology / Peritoneum / Plasminogen activator inhibitors / Pyruvaldehyde / Pyruvaldehyde - toxicity / Reactive Oxygen Species / Rodents / Science / Science (multidisciplinary)