title: Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation.
abstract: OBJECTIVE
  Nephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease after administration of gadolinium (Gd)-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, Gd deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such as silica or asbestos, activate the nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and initiate interleukin (IL)-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation.
  
  
  METHODS
  Bone marrow derived macrophages from C57BL/6, Nlrp3(-/-) and Asc(-/-) mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and interferon (IFN)γ-polarised macrophages by ELISA, quantitative real time (qRT)-PCR and NanoString nCounter analysis. Furthermore, C57BL/6 and Nlrp3(-/-)mice were intraperitoneally injected with GBCA and recruitment of inflammatory cells to the peritoneum was analysed by fluorescence-activated cell sorting (FACS).
  
  
  RESULTS
  Free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β secretion in vitro. Gd-diethylenetriaminepentaacetic acid also induces the recruitment of neutrophils and inflammatory monocytes to the peritoneum in vivo. Gd activated IL-4-polarised macrophages more effectively than IFNγ-polarised macrophages, which preferentially expressed genes known to downregulate inflammasome activity.
  
  
  CONCLUSIONS
  These data suggest that Gd released from GBCAs triggers a NLRP3 inflammasome-dependent inflammatory response that leads to fibrosis in an appropriate clinical setting. The preferential activation of IL-4-differentiated macrophages is consistent with the predominantly fibrotic presentation of NSF.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt-Lauber
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.affiliation: Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hani H
authors.initials: HH
authors.lastname: Abujudeh
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Vladimer
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Anette
authors.initials: A
authors.lastname: Christ
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA Institute of Innate Immunity, University of Bonn and German Center of Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0002-8970-4260
authors.initials: J
authors.lastname: Kay
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D003287:Contrast Media / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D005682:Gadolinium / Q000009:adverse effects / Q000494:pharmacology*; D019786:Gadolinium DTPA / Q000009:adverse effects / Q000494:pharmacology; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology; D053583:Interleukin-1beta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D009942:Organometallic Compounds / Q000009:adverse effects / Q000494:pharmacology; D010537:Peritoneum / Q000187:drug effects* / Q000276:immunology; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003287:Contrast Media; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009942:Organometallic Compounds; C498534:Pycard protein, mouse; C064925:gadodiamide; D005682:Gadolinium; D019786:Gadolinium DTPA; C038958:gadolinium chloride
keywords: Cytokines; Inflammation; Magnetic Resonance Imaging