The NLRP3 Inflammasome Has a Critical Role in Peritoneal Dialysis-Related Peritonitis

• Published in: Journal of the American Society of Nephrology 2017-07, Vol.28 (7), p.2038-2052
• Main Authors: Hautem, Nicolas, Morelle, Johann, Sow, Amadou, Corbet, Cyril, Feron, Olivier, Goffin, Eric, Huaux, François, Devuyst, Olivier
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Animals; Basic Research; Female; Humans; Inflammasomes - physiology; Interleukin-1beta - physiology; Male; Mice; Middle Aged; NLR Family, Pyrin Domain-Containing 3 Protein - physiology; Peritoneal Dialysis; Peritonitis - etiology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2016070729

Bacterial peritonitis remains the main cause of technique failure in peritoneal dialysis (PD). During peritonitis, the peritoneal membrane undergoes structural and functional alterations that are mediated by IL-1 The NLRP3 inflammasome is a caspase-1-activating multiprotein complex that links sensing of microbial and stress products to activation of proinflammatory cytokines, including IL-1 The potential roles of the NLRP3 inflammasome and IL-1 in the peritoneal membrane during acute peritonitis have not been investigated. Here, we show that the NLRP3 inflammasome is activated during acute bacterial peritonitis in patients on PD, and this activation associates with the release of IL-1 in the dialysate. In mice, lipopolysaccharide- or -induced peritonitis led to IL-1 release in the peritoneal membrane. The genetic deletion of , which encodes NLRP3, abrogated defects in solute transport during acute peritonitis and restored ultrafiltration. In human umbilical vein endothelial cells, IL-1 treatment directly enhanced endothelial cell proliferation and increased microvascular permeability. These effects require endothelial IL-1 receptors, shown by immunofluorescence to be expressed in peritoneal capillaries in mice. Furthermore, administration of the IL-1 receptor antagonist, anakinra, efficiently decreased nitric oxide production and vascular proliferation and restored peritoneal function in mouse models of peritonitis, even in mice treated with standard-of-care antibiotherapy. These data demonstrate that NLRP3 activation and IL-1 release have a critical role in solute transport defects and tissue remodeling during PD-related peritonitis. Blockade of the NLRP3/IL-1 axis offers a novel method for rescuing morphologic alterations and transport defects during acute peritonitis.