Elsevier

Life Sciences

Volume 100, Issue 1, 28 March 2014, Pages 1-8
Life Sciences

Minireview
Innate immunity and cardiomyocytes in ischemic heart disease

https://doi.org/10.1016/j.lfs.2014.01.062Get rights and content

Abstract

Myocardial ischemia/reperfusion (I/R) is the most common cause of myocardial inflammation, which is primarily a manifestation of the innate immune responses. Innate immunity is activated when pattern recognition receptors (PRRs) respond to molecular patterns common to microbes and to danger signals expressed by injured or infected cells, so called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The expression of various PRRs in cardiomyocytes and the release of DAMPs from cardiomyocytes subjected to I/R injury, through active mechanisms as well as passive processes, enable cardiomyocytes to generate innate immune responses. Studies in isolated heart and cardiomyocytes have confirmed the inflammatory and functional effects of cardiac PRRs especially Toll-like receptors in response to I/R-derived DAMPs, such as heat shock proteins. This review addresses the active role of cardiomyocytes in mediating innate inflammatory responses to myocardial I/R. We propose that cardiomyocytes act as innate immune cells in myocardial I/R injury.

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).

References (93)

  • G.I. Lancaster et al.

    Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins

    J Biol Chem

    (2005)
  • B. Lemaitre et al.

    The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults

    Cell

    (1996)
  • Y. Li et al.

    Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4

    J Biol Chem

    (2011)
  • G. Novo et al.

    Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction

    Transl Res

    (2011)
  • J.S. Park et al.

    Involvement of Toll like receptors 2 and 4 in cellular activation by high mobility group box 1 protein

    J Biol Chem

    (2004)
  • A. Rossini et al.

    HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells

    J Mol Cell Cardiol

    (2008)
  • O. Takeuchi et al.

    Pattern recognition receptors and inflammation

    Cell

    (2010)
  • R.M. Vabulas et al.

    Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells

    J Biol Chem

    (2001)
  • Y. Wang et al.

    Regulation of heat shock protein 60 and 72 expression in the failing heart

    J Mol Cell Cardiol

    (2010)
  • Y. Wang et al.

    Pirfenidone attenuates cardiac fibrosis in a mouse model of TAC-induced left ventricular remodeling by suppressing nlrp3 inflammasome formation

    Cardiology

    (2013)
  • R. Zhan et al.

    Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes

    Biochem Biophys Res Commun

    (2009)
  • H. Zhu et al.

    Rac1 mediates sex difference in cardiac tumor necrosis factor-alpha expression via NADPH oxidase-ERK1/2/p38 MAPK pathway in endotoxemia

    J Mol Cell Cardiol

    (2009)
  • M. Andrassy et al.

    High-mobility group box-1 in ischemia–reperfusion injury of the heart

    Circulation

    (2008)
  • L. Ao et al.

    Myocardial TLR4 is a determinant of neutrophil infiltration after global myocardial ischemia: mediating KC and MCP-1 expression induced by extracellular HSC70

    Am J Physiol

    (2009)
  • F. Arslan et al.

    Innate immune signaling in cardiac ischemia

    Nat Rev Cardiol

    (2011)
  • F. Arslan et al.

    Myocardial ischemia/reperfusion injury is mediated by leukocytic Toll-like receptor-2 and reduced by systemic administration of a novel anti-Toll-like receptor-2 antibody

    Circulation

    (2010)
  • O. Avlas et al.

    Toll-like receptor 4 stimulation initiates an inflammatory response that decreases cardiomyocyte contractility

    Antioxid Redox Signal

    (2011)
  • G. Baumgarten et al.

    Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia

    Shock

    (2006)
  • B.W. Binck et al.

    Bone marrow-derived cells contribute to contractile dysfunction in endotoxic shock

    Am J Physiol Heart Circ Physiol

    (2005)
  • J.H. Boyd et al.

    Toll-like receptor stimulation in cardiomyocytes decreases contractility and initiates an NF-κB dependent inflammatory response

    Cardiovasc Res

    (2006)
  • W.F. Cai et al.

    Intracellular or extracellular heat shock protein 70 differentially regulates cardiac remodelling in pressure overload mice

    Cardiovasc Res

    (2010)
  • B. Dybdahl et al.

    Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction

    Heart

    (2005)
  • B. Dybdahl et al.

    Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through Toll-like receptor-4

    Circulation

    (2002)
  • Y. Evdokimovskaya et al.

    Secretion of the heat shock proteins HSP70 and HSC70 by baby hamster kidney (BHK-21) cells

    Cell Biol Int

    (2010)
  • Y. Feng et al.

    Toll-like receptors and myocardial inflammation

    Int J Inflamm

    (2011)
  • M. Fernández-Velasco et al.

    NOD1 activation induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis

    PLoS One

    (2012)
  • L. Franchi et al.

    Sensing and reacting to microbes via the inflammasomes

    Nat Immunol

    (2012)
  • S. Frantz et al.

    Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium

    J Clin Invest

    (1999)
  • A. Funayama et al.

    Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure

    Cardiovasc Res

    (2013)
  • S. Gupta et al.

    Cytosolic HSP60, hypoxia, and apoptosis

    Circulation

    (2002)
  • S. Gupta et al.

    HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway

    Am J Physiol Heart Circ Physiol

    (2007)
  • T. Ha et al.

    Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism

    Cardiovasc Res

    (2008)
  • T. Ha et al.

    Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-κB activation

    Am J Physiol Heart Circ Physiol

    (2011)
  • L.E. Hightower et al.

    Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins

    J Cell Physiol

    (1989)
  • S. Kapadia et al.

    Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration

    J Clin Invest

    (1995)
  • S.R. Kapadia et al.

    Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium

    Circ Res

    (1997)
  • Cited by (74)

    • Innate and adaptive immunity in acute myocarditis

      2024, International Journal of Cardiology
    • Molecular and cellular pathophysiology of circulating cardiomyocyte-specific cell free DNA (cfDNA): Biomarkers of heart failure and potential therapeutic targets

      2023, Genes and Diseases
      Citation Excerpt :

      In order to strive, cardiomyocytes initially respond by structural and functional remodelling which is characterised by increased cell size and mass as an adaptive mechanism—referred to hypertrophy.22,23 Persisting mechanical stress by biochemical stressors in cardiomyocyte triggers cell death pathways including autophagy, apoptosis and necrosis24 thereby releasing inflammatory DAMP molecules and triggering the pathological form of hypertrophy3,25 (Fig. 1A). The intercellular communication by DAMPs triggers positive feedback within myocardial resident cells leading to an inflammatory burst.

    • Cadherin-11 and cardiac fibrosis: A common target for a common pathology

      2021, Cellular Signalling
      Citation Excerpt :

      If clearance of inflammatory cells and differentiation of myofibroblasts into matrifibrocytes does not occur, feedforward signaling begins whereby inflammatory cells and myofibroblasts continue to promote fibrosis through chronically activated proinflammatory and profibrotic signaling pathways. Cardiovascular diseases such as heart failure, aortic valve disease, and atherosclerosis are often initiated by acute inflammatory reactions caused by stressed and necrotic cardiomyocytes as a protective response to infection, injuries such as myocardial infarction, or stress conditions such as hypertension [16,25,26]. As mentioned previously, stressed cardiac cells release DAMPs such as heat-shock proteins, degraded ECM molecules, and DNA fragments.

    • Innate Immune Receptors, Key Actors in Cardiovascular Diseases

      2020, JACC: Basic to Translational Science
    View all citing articles on Scopus
    View full text