Abstract 13715: Colchicine Acutely Suppresses the NLRP3 Inflammasome in Acute Coronary Syndrome Patients Monocytes

Abstract

Objectives: Inflammasome activation, with subsequent release of pro-inflammatory cytokines IL-1β and IL-18, has recently been implicated in atherosclerosis-associated inflammation. Here, in acute coronary syndrome (ACS) patients, we assessed (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. Methods: ACS patients (n=21) were randomized to oral colchicine (1.5mg) or no treatment, and compared with untreated healthy controls. Venous samples were drawn pre- (day 1) and 24h post- (day 2) treatment. Cultured monocytes were stimulated with ATP which facilitates the release of cleaved cytokines. Analysis of key inflammasome markers was performed in cell media and lysates. Results: Monocytes from untreated ACS patients secreted significantly higher levels of cleaved IL-1β and IL-18 vs healthy controls (p<0.05 for both; Fig A). Colchicine treatment in ACS patients markedly reduced intracellular pro- and cleaved IL-1β protein levels as well as secreted cleaved IL-1β protein levels (Fig A) vs pre-treatment levels. Colchicine treatment significantly reduced pro-caspase-1 mRNA levels and secreted caspase1 protein levels (p<0.05) vs untreated patients (Fig B). IL-18 levels were unaffected by treatment. In untreated ACS patients, inflammasome-related protein levels did not significantly change between day 1 and day 2 Conclusion: We show here, for the first time, that (1) monocytes from ACS patients are “primed” to secrete inflammasome-related cytokines and (2) short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing cellular protein secretion of IL-1β. These data, therefore, provide mechanistic insights into a potential role for colchicine in suppressing coronary inflammation in ACS patients.