Figure 1. Inflammasome activation pathway. Acute myocardial infarction (AMI) causes the release of danger signals including damage-associated molecular pattern molecules (DAMPs) and ATP in response to tissue damage, cell death and lack of blood and nutrient supply to the heart [a].

Extracellular ATP activates purinergic receptor P2X ligand-gated ion channel 7 (P2RX7; P2X7), causing the channel to open, resulting in K+ efflux from the cell [b(1)]. According to the findings from Mezzaroma et al., this process occurs in cardiomyocytes. Extracellular K+ activates the membrane receptor pannexin 1 (PANX1), opening the channel and allowing transport of DAMPs into the cardiomyocyte [b(2)].

DAMPs serve as direct activating ligands for NLR family pyrin domain containing 3 (NLRP3; NALP3). Activation of NLRP3 induces PYD and CARD domain containing (PYCARD; ASC) recruitment and inflammasome formation [b(3)]. Inflammasome formation causes cleavage of procaspase-1 into IL-1 b-converting enzyme (CASP1), causing downstream activation of inflammatory cytokines including IL-1b and IL-18 [b(4)].

Release of IL-1b and other cytokines from cardiomyocytes ultimately induces immune cell recruitment to the heart, inflammation and cardiac remodeling [c].

Mezzaroma et al. show that antagonizing P2X7 prevents inflammasome formation and cardiac remodeling (i). IL-1b inhibitors block immune cell recruitment downstream, blocking some cardiovascular inflammation and remodeling (ii).