Targeting inflammatory pathways in myocardial infarction

Abstract

Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signalling and triggering an intense inflammatory reaction. Infiltrating leucocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels, the geometric, functional and molecular alterations associated with postinfarction remodelling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the postinfarction inflammatory reaction may be crucial to protect the myocardium from dilative remodelling and progressive dysfunction. Inhibition and resolution of postinfarction inflammation involve mobilization of inhibitory mononuclear cell subsets and require activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the postinfarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischaemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodelling. Given the pathophysiologic complexity of postinfarction remodelling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and monocyte chemoattractant protein-1) may be effective in patients with defective resolution of postinfarction inflammation who exhibit progressive dilative remodelling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies.

Keywords: Animal models; cytokine; inflammation; leucocytes; myocardial infarction; remodelling.

© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

Figures

Figure 1

Initiation of the inflammatory response following myocardial infarction. Necrotic cardiomyocytes (CM) and damaged extracellular matrix release danger signals (DAMPS) triggering the complement cascade and activating TLR/IL-1 signaling. Resident mast cells (MC) degranulate and release preformed pro-inflammatory mediators, whereas activation endothelial cells (EC) and fibroblasts (Fib) results in induction of chemokines and cytokines. Leukocytes are recruited in the infarcted heart through activation of a multi-step adhesion cascade. Circulating neutrophils are captured by the activated endothelium (1) and roll on the endothelial surface (2) through interactions that involve the selectins. Neutrophils “sense” chemokines immobilized on the endothelial surface and exhibit integrins activation. Firm adhesion of the leukocyte to the endothelium follows through interactions that involve integrins and ICAM-1 (3). Transmigration of the neutrophils across the endothelial layer (4) is a complex process that involved the JAMs, ICAM-1 and VE-cadherin (see text). After extravasation into the infarct (5), neutrophils play an important role in clearance of the tissue from dead cells and matrix debris. (Additional symbol: ROS, reactive oxygen species).

Figure 2

Resolution of the post-infarction inflammatory response involves activation of multiple inhibitory signals and recruitment, or transdifferentiation, of leukocyte subpopulations with suppressive properties. Expression of GDF-15 may reduce neutrophil integrin (Int) activation, inhibiting adhesive interactions between leukocytes and the endothelium. Recruitment of regulatory T cells (Tregs) and inhibitory monocyte subpopulations through distinct chemokine (CC)/chemokine receptor interactions may result in infiltration of the infarct with anti-inflammatory mononuclear cells. Clearance of apoptotic neutrophils by macrophages may result in secretion of inhibitory mediators, including IL-10, TGF-β and lipoxins. Infarct macrophages exhibit activation of endogenous signals (such as IRAK-M) that suppress inflammatory and immune responses (see text).