Danger signals in the initiation of the inflammatory response after myocardial infarction

Abstract

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.

Figure 1

DAMP signaling through different PRRs. TLR activation by DAMPS triggers adaptor proteins MyD88, TRIF, TIRAP, or TRAM to activate various transcriptions factors. The subsequent translocation of NF-κB and MAPK leads to the production of several proinflammatory cytokines. TRIF-dependent activation of transcription factors IRF3 and IRF7 results in the induction of type I interferon. Additionally, the TLR- NF-κB pathway can induce the transcription of pro-IL-1β, pro-IL-18, and other components of the inflammasome pathway. Inflammasome activation is considered to depend on two distinct signals. The first signal via TLR and this might be the rate limiting step for inflammasome assembly and activity; the second signal via NLR which is responsible for inflammasome assembly, caspase-1 activation, and secretion of IL-1β and IL-18. Activation of NOD receptors results in activation of the NF-κB pathway.

Figure 2

Proposed simplified mediators of danger signal release during myocardial infarction. Necrotic cells in the myocardium are leaky and release a subset of DAMPs, for instance, mtDNA and the DNA binding protein HMGB1. Furthermore, viable cells get stress signals from their surroundings and start to produce and secrete a range of proteins. These cells start the production of the EDA splice variant of fibronectin, HSPs and the matricellular proteins CCN1, osteopontin, galectins, and tenascin-C. Both the proteins released by necrotic cells and the produced proteins by stressed cells are able to activate or aggravate the immune response in the heart following MI.