title: Interleukin-1β blockade improves cardiac remodelling after myocardial infarction without interrupting the inflammasome in the mouse.
abstract: The formation of the cryopyrin inflammasome in the heart induces an intense inflammatory response during acute myocardial infarction (AMI), which mediates further damage and promotes adverse cardiac remodelling. Active interleukin-1β (IL-1β) is a key product of the inflammasome, being cleaved by active caspase-1. The aim of this study was to dissect the role of IL-1β from that of the inflammasome by using a neutralizing monoclonal antibody directed against IL-1β and measuring the intensity of the inflammatory response, the activity of caspase-1 in the inflammasome, cardiomyocyte apoptosis and cardiac remodelling in a mouse model of non-reperfused AMI. A mouse monoclonal IgG2a antibody directed against IL-1β (IL-1β-AB; 10 mg kg(-1)) was given i.p. immediately after surgery and repeated 1 week later. Cardiac tissue was analysed at 72 h after surgery in a subgroup of mice for inflammasome aggregates and caspase-1 activity (inflammasome) and for DNA fragmentation and caspase-3 activity (apoptosis). All sham-operated mice were alive at 10 weeks, whereas 40% of the control-antibody-treated mice and 30% of the IL-1β-AB-treated mice died during the 4 weeks after surgery. When compared with vehicle, treatment with the IL-1β-AB did not affect inflammasome formation or caspase-1 activation in the heart tissue at 72 h after AMI nor circulating plasma IL-6 levels, but did inhibit cardiomyocyte apoptosis, limit left ventricular enlargement by 40% (P < 0.01) and improve systolic dysfunction by 17% (P < 0.01) after AMI. These findings suggest that IL-1β mediates the deleterious effects on the heart during the sterile inflammatory response.
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, 1200 East Broad Street, Box 980281, Richmond, VA 23298, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053148:Caspase 3; D020170:Caspase 1