title: The NLRP3 Inflammasome Has a Critical Role in Peritoneal Dialysis-Related Peritonitis.
abstract: 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-1βThe NLRP3 inflammasome is a caspase-1-activating multiprotein complex that links sensing of microbial and stress products to activation of proinflammatory cytokines, including IL-1βThe potential roles of the NLRP3 inflammasome and IL-1βin 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-1βin the dialysate. In mice, lipopolysaccharide- orEscherichia coli-induced peritonitis led to IL-1βrelease in the peritoneal membrane. The genetic deletion ofNalp3, which encodes NLRP3, abrogated defects in solute transport during acute peritonitis and restored ultrafiltration. In human umbilical vein endothelial cells, IL-1βtreatment directly enhanced endothelial cell proliferation and increased microvascular permeability. Thesein vitroeffects require endothelial IL-1 receptors, shown by immunofluorescence to be expressed in peritoneal capillaries in mice. Furthermore, administration of the IL-1βreceptor 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-1βrelease have a critical role in solute transport defects and tissue remodeling during PD-related peritonitis. Blockade of the NLRP3/IL-1βaxis offers a novel method for rescuing morphologic alterations and transport defects during acute peritonitis.
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hautem
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.|Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; and.
authors.forename: Johann
authors.initials: J
authors.lastname: Morelle
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.|Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; and.
authors.forename: Amadou
authors.initials: A
authors.lastname: Sow
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Cyril
authors.initials: C
authors.lastname: Corbet
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.affiliation: Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Goffin
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Huaux
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; olivier.devuyst@uzh.ch.|Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; and.|Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D010530:Peritoneal Dialysis; D010538:Peritonitis / Q000209:etiology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse
keywords: Interleukin-1; anakinra; cytokines; peritoneal membrane; ultrafiltration; vascular permeability