MinireviewInnate immunity and cardiomyocytes in ischemic heart disease
Graphical abstract
Introduction
Ischemic heart disease is the leading cause of heart failure. Growing evidence supports that innate immunity plays a critical role in myocardial ischemia and the development of heart failure. A mild to moderate innate immune response may limit the extent of cardiac injury and facilitate tissue repair, whereas an excessive response is likely to be deleterious (Mann, 2011). The persistent activation of innate immune responses, as characterized by progressive increases in serum inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6, is associated with the development of heart failure.
The innate immunity, which manifests as inflammation, is typically generated by innate immune cells, including neutrophils, monocytes, macrophages and dendritric cells. It is activated when pattern recognition receptors (PRRs) in immune cells respond to conserved motifs of invading pathogens and nonself elements, namely pathogen-associated molecular patterns (PAMPs). PPRs may also respond to endogenous molecular patterns released during cellular injury or death, namely damage-associated molecular patterns (DAMPs), and subsequently induce sterile inflammation (Rock et al., 2010).
Recently, several lines of data have suggested that cardiomyocytes can be a significant source of innate immune responses. First, the release of multiple DAMPs from stressed cardiomyocytes through active pathways has been found. Second, the expression of a variety of PRRs has been identified in both basal and stressed cardiomyocytes. Third, activation of cardiomyocyte PRRs by either PAMPs or DAMPs leads to inflammatory signaling and cytokine expression, similar to the case for immune cells. The current review focuses on the active role of the heart in inducing and coordinating innate responses to myocardial ischemia/reperfusion (I/R) (Fig. 1).
Section snippets
Overview of innate immunity and the heart
The immune system was originally described to function by making a distinction between self and nonself. In the relatively recent ‘danger model’ of immunity, the system is believed to react to ‘danger signals’, either self or nonself (Matzinger, 2002). The exogenous ‘danger signals’, so called PAMPs, are highly conserved motifs in microbial pathogens, such as lipopolysaccharide (LPS), peptidoglycan, lipoteichoic acid and flagellin of bacteria, mannan of yeast, chitin and ergosterol of fungi,
PRRs in cardiomyocytes
The discovery of PRRs has greatly advanced our understanding of how the body recognizes pathogens and starts immune responses. PRRs are a large family, including transmembrane receptors such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), as well as cytoplasmic receptors such as the retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), NLRs, and absent-in-melanoma (AIM) 2 receptors (Rathinam et al., 2010, Takeuchi and Akira, 2010). These PRRs are expressed not only in
DAMPs generated by ischemic cardiomyocytes
Most of our current knowledge of endogenous DAMPs is limited to the DAMPs linked to TLRs, while little is known about the DAMPs linked to other PRRs. Theoretically, every molecule that normally localizes within cells can potentially be a DAMP when released to the extracellular space. The dynamic alterations of extracellular matrix (ECM) resulting from myocardial I/R can also generate DAMP molecules. Either ECM degradation products or de novo synthesized matrix molecules may function as
Conclusion
In terms of the ability to generate DAMPs and express functional PRRs, the heart functions as an active innate immune organ in myocardial I/R. Rather than passively being a target of inflammation, the active involvement of the heart in inducing and regulating inflammation provides important insights in myocardial I/R injury, and opens up a novel field for the investigation of cardiac inflammation, which can lead to new therapeutic interventions.
Conflict of interest statement
None declared.
Acknowledgments
This work was supported by the National Institutes of Health [grant numbers HL077281, HL079071] and a Merit Award from the Department of Veterans Affairs (all to AAK), and the National Natural Science Foundation of China (grant numbers 31071023 and 81370348, both to LL).
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