Interleukin-1 in cardiac injury, repair, and remodeling: pathophysiologic and translational concepts

In the infarcted myocardium, necrotic cardiomyocytes release danger signals activating an intense inflammatory reaction that serves to clear the wound from dead cells and matrix debris, but may also extend injury. A growing body of evidence suggests an important role for members of the Interleukin (IL)-1 family in injury, repair and remodeling of the infarcted heart. This review manuscript discusses the pathophysiologic functions of IL-1 in the infarcted and remodeling myocardium and its potential role as a therapeutic target in patients with myocardial infarction. Dead cardiomyocytes release IL-1a that may function as a crucial alarmin triggering the post-infarction inflammatory reaction. IL-1b is markedly upregulated in the infarcted myocardium; activation of the inflammasome in both cardiomyocytes and interstitial cells results in release of bioactive IL-1b in the infarcted area. Binding of IL-1 to the type 1 receptor triggers an inflammatory cascade, inducing recruitment of pro-inflammatory leukocytes and stimulating a matrix-degrading program in fibroblasts, while delaying myofibroblast conversion. IL-1 mediates dilative remodeling following infarction and may play a role in the pathogenesis of post-infarction heart failure. As the wound is cleared from dead cells and matrix debris, endogenous inhibitory signals suppress the IL-1 response resulting in repression of inflammation and resolution of the inflammatory infiltrate. Other members of the IL-1 family (such as IL-18 and IL-33) are also implicated in regulation of the inflammatory and reparative response following myocardial infarction. IL-18 may participate in pro-inflammatory signaling, whereas IL-33 may exert cytoprotective effects. Early clinical trials suggest that IL-1 blockade may be a promising therapeutic strategy for patients with myocardial infarction.