Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation

• Published in: Clinical science (1979) Vol. 130; no. 14; pp. 1237 - 1246
• Main Authors: Robertson, Stacy, Martínez, Gonzalo J, Payet, Cloe A, Barraclough, Jennifer Y, Celermajer, David S, Bursill, Christina, Patel, Sanjay
• Format: Journal Article
• Language: English
• Published: England 01.07.2016
• Subjects: Acute Coronary Syndrome - drug therapy; Acute Coronary Syndrome - immunology; Acute Coronary Syndrome - metabolism; Aged; Aged, 80 and over; Caspase 1 - metabolism; Cells, Cultured; Colchicine - pharmacology; Colchicine - therapeutic use; Female; Humans; Interleukin-18 - secretion; Interleukin-1beta - secretion; Male; Middle Aged; Monocytes - drug effects; Monocytes - physiology; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; atherosclerosis; monocytes; colchicine; inflammasome; acute coronary syndromes
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20160090

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.