During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research. 1. Introduction In 1994, Matzinger postulated a theory that the immune system may not be evolved to distinguish between self and non-self, but rather sense “danger” [1]. Danger signals, besides pathogen associated molecular patterns (PAMPs), can be intracellular molecules that are normally not exposed to the immune system, for example, cardiac myosin and mitochondrial DNA, but also proteins that are only upregulated during injury, such as heat shock proteins (HSP). Danger signals can therefore be divided into constitutive and inducible. Furthermore, danger signals can be classified as truly primal initiators, which do not require previous activation of antigen presenting cells (APC) or positive feedback signals, which can amplify or convert an ongoing inflammatory response [2]. This danger model explains the inflammatory response following myocardial infarction (MI), a situation where danger associated molecular patterns (DAMPs), and not pathogens, activate the immune system. For instance, extracellular matrix breakdown products released by the damaged myocardium and constituents of dying cardiomyocytes serve as danger signals in the infarcted myocardium, activating an inflammatory reaction. A certain amount
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