Abstract 14205: Myocardial Injury Induces AIM2 Inflammasome Expression in Neutrophil Granulocytes in Patients With Acute Myocardial Infarction
Background: Neutrophils (PMN) are primed and recruited to sites of sterile inflammation, including myocardial tissue injury following acute myocardial infarction (AMI). It has been shown that specific intracellular protein complexes, so-called inflammasomes, can initiate an inflammatory response by sensing host-derived danger signals (DAMPs). We investigated inflammasome expression in PMN and its role in induction of a sterile inflammatory response in patients with AMI.
Methods and Results: We analyzed 60 patients (pts) with AMI (30 STEMI, 30 NSTEMI) and 30 pts with stable coronary heart disease (CHD) prior to and 24 hours after PCI. 20 healthy donors served as controls (Ctrl). Inflammasome-related mRNA and protein expression (NLRP3, AIM2, NLRC5, ASC, IL-1b, IL-18) in PMN was analyzed by RT-PCR and immunoassays. In an in-vitro model, PMN from healthy donors were stimulated with DAMPs (ATP, dsDNA). Kinetics of inflammasome expression in-vivo was analysed in 5 patients undergoing transcoronary ablation of septal hypertrophy (TASH), a model of human AMI. PMN were collected before and at 15, 30, 45, 60, 90 min, and 2, 4, 8, and 24 h after septal branch occlusion.
Expression of mRNA for absent in melanoma 2 (AIM2) inflammasome was significantly increased in PMN (but not in monocytes or lymphocytes) from AMI pts as opposed to stable CHD pts (p=0.02) or Ctrl (p<0.01). AIM2 expression was higher in NSTEMI than in STEMI pts (p=0.009 and p=0.0001 vs. Ctrl). This activation was sustained within 24 h after PCI (r2=0.8; p<0.0001). AIM2 protein expression was significantly increased in STEMI (fold change vs. Ctrl: 5.6±1; p=0.008) and NSTEMI pts (7.2±0.6; p=0.016). AIM2 activation was reflected by enhanced processing of its downstream target, IL-18, in AMI pts. DAMP stimulation resulted in a 3-fold increase in AIM2 expression accompanied by caspase-1 dependent release of IL-18. In a TASH model, mRNA expression of AIM2 in PMN doubled already 15 min after ischemia induction and was significantly increased at 2 h (5.5-fold vs. baseline; p=0.021).
Conclusion: AIM2 is a novel target involved in neutrophil-mediated response to sterile injury. Our data suggest that inflammasome induction in PMN contributes to the early inflammatory response in patients with myocardial infarction.
- © 2013 by American Heart Association, Inc.