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

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

Nikolaos G Frangogiannis. Discoveries (Craiova). 2015 Jan-Mar.

Abstract

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-1α that may function as a crucial alarmin triggering the post-infarction inflammatory reaction. IL-1β is markedly upregulated in the infarcted myocardium; activation of the inflammasome in both cardiomyocytes and interstitial cells results in release of bioactive IL-1β 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.

Keywords: Myocardial infarction; cardiac remodeling; cytokine; inflammation.

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Conflict of interest statement

Conflict of interests: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Figure 1. Regulation of IL-1 signaling by native inhibitors and decoy receptors

IL-1α, or IL-1β binds to IL-1R1 and forms a complex with IL-1RAcP, recruiting myeloid differentiation protein 88 (MyD88) and triggering the signaling cascade that involves IRAK-1 and IRAK-4 activation (A). The endogenous inhibitor IL-1Ra also binds to IL-1R1, but does not signal because it fails to form a complex with IL-1RAcP (B). IL-1 binding to the decoy receptor IL-1R2 does not result in stimulation of a signaling cascade, as this receptor lacks a cytoplasmic segment (C).

Figure 2
Figure 2. Figure 2. The cellular targets of IL-1 in myocardial infarction.

IL-1α (released by necrotic cardiomyocytes) and IL-1β (newly synthesized and secreted by resident myocardial cells and infiltrating leukocytes) signal by activating IL-1R1. IL-1 induces cardiomyocyte apoptosis and suppresses cardiomyocyte function, stimulates a matrix-degrading pro-inflammatory program in cardiac fibroblasts and delays fibroblast to myofibroblast transdifferentiation, induces cytokine expression in macrophages, mediates leukocyte recruitment by inducing adhesion molecule expression by endothelial cells and prolongs neutrophil survival.

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