title: Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart.
abstract: OBJECTIVE
  The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death. Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury.
  
  
  RESULTS
  We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice). The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome were significantly less expressed in the heart compared with the spleen. Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome (priming), measured using real-time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P < 0.01 for mutant vs. wild-type mice).
  
  
  CONCLUSIONS
  The signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction.
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA stoldo2@vcu.edu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Peña
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sonnino
authors.affiliation: Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1220 East Broad Street, Richmond, VA 23298, USA Victoria Johnson Research Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1
keywords: Cardiomyopathy; Caspase-1; Cryopyrinopathy; Inflammasome; NLRP3; Priming