title: Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation.
abstract: Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are 'primed' to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β.
authors.affiliation: Heart Research Institute, Sydney, New South Wales 2042, Australia Sydney Medical School, The University of Sydney, New South Wales 2006, Australia Sanjay.Patel@sswahs.nsw.gov.au stacy.robertson@hri.org.au.
authors.forename: Stacy
authors.initials: S
authors.lastname: Robertson
authors.affiliation: Sydney Medical School, The University of Sydney, New South Wales 2006, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia División de Enfermedades Cardiovasculares, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Gonzalo J
authors.initials: GJ
authors.lastname: Martínez
authors.affiliation: Heart Research Institute, Sydney, New South Wales 2042, Australia.
authors.forename: Cloe A
authors.initials: CA
authors.lastname: Payet
authors.affiliation: Heart Research Institute, Sydney, New South Wales 2042, Australia Sydney Medical School, The University of Sydney, New South Wales 2006, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Barraclough
authors.affiliation: Heart Research Institute, Sydney, New South Wales 2042, Australia Sydney Medical School, The University of Sydney, New South Wales 2006, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Celermajer
authors.affiliation: Heart Research Institute, Sydney, New South Wales 2042, Australia Sydney Medical School, The University of Sydney, New South Wales 2006, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Bursill
authors.affiliation: Heart Research Institute, Sydney, New South Wales 2042, Australia Sydney Medical School, The University of Sydney, New South Wales 2006, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia Sanjay.Patel@sswahs.nsw.gov.au stacy.robertson@hri.org.au.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors*
chemical_list: D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020170:Caspase 1; D003078:Colchicine
keywords: acute coronary syndromes; atherosclerosis; colchicine; inflammasome; monocytes