Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia

Fallach, Reut; Shainberg, Asher; Avlas, Orna; Fainblut, Michael; Chepurko, Yelena; Porat, Eyal E.; Hochhauser, Edith

doi:10.1016/j.yjmcc.2010.02.020

Cited by 130 publications

(111 citation statements)

References 39 publications

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“…The most common cause of CHF is ischaemic heart disease. The literature reports that TLR4 expression increases within days of MI 12, 14. We previously observed enhanced TLR4 expression after short‐term ischaemia in cultured cardiomyocytes, as well as intact heart 15.…”

Section: Introductionmentioning

confidence: 64%

“…By using chimeric mice, Fallach et al . 14 and Avlas et al . 35 reported that cardiomyocyte TLR4, rather than leucocyte TLR4, plays a greater role in cardiac inflammation and dysfunction caused by either LPS or coronary artery ligation.…”

Section: Discussionmentioning

confidence: 92%

“…Fallach et al . observed increased immunohistochemical staining for TLR4 in mice hearts at 4 hrs and 24 hrs after MI 14. In mice hearts after 4 days of MI, Frantz et al .…”

Section: Discussionmentioning

confidence: 92%

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Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

137

108

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It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.

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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

137

108

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“…Knockout mouse studies have proven useful for identifying specific roles for DAMP receptors in modulating cardiac remodelling after injury or stress (summarised in Table 1). Global knockout or deficiency of TLR2 [34][35][36][37][38][39], TLR3 [40,41] and TLR4 [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] generally confers improvement of cardiac function and less adverse remodelling after injury, although detrimental effects have also been reported in TLR2 knockout mice [57]. In contrast to the perceived detrimental roles of TLRs 2, 3 and 4 in post-MI remodelling, a recent study suggested that TLR5 may play a beneficial role in protecting the heart from ischaemia/reperfusion injury [58].…”

Section: Damp Receptors and Cardiac Remodellingmentioning

confidence: 99%

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

166

124

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Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

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“…Growing evidence has demonstrated that TLRs play a critical role in myocardial ischemia/reperfusion npg (I/R) injury. Specifically, a deficiency of TLR4 protects the myocardium from ischemic injury whereas modulation of TLR2 induces cardioprotection against ischemic insult [10,11]. Recent work suggests a role for NLR protein, Nlrp3, in the inflammation-and cardiac injury-induced post ischemia.…”

mentioning

confidence: 99%

Indigestible mitochondria cause heartburn

Gottlieb

Linton

2012

Cell Res

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The link between impaired autophagic flux (autophagus interruptus), damaged mitochondria, and myocardial inflammation has been further tightened with the recent paper by Oka and colleagues, in which failure to degrade mitochondrial DNA exacerbated myocardial inflammation in the context of pressure overload. Using mice with cardiac-specific deletion of the lysosomal DNase II that were subjected to aortic banding, Otsu's group showed that mitochondrial DNA accumulated in lysosomes and resulted in TLR9-dependent production of inflammatory cytokines.The link between autophagy, mitochondria, and inflammation in the heart has been further tightened with the recent paper in Nature by Oka et al [1]. In this work, Otsu's team showed that mitochondrial DNA (mtDNA) that escapes autophagy led to the activation of TLR9 and inflammation. Mice with cardiac-specific deletion of lysosomal DNase II (DNase2a -/-) developed accelerated myocarditis and heart failure after the induction of pressure overload with thoracic transverse aortic constriction (TAC). Cardiomyocytes in TAC-treated DNase2a -/-mice showed increased expression of IL-1β and IL-6, which was followed by infiltration of CD68 + macrophages and Ly6G + cells.

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Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia

Cited by 130 publications

References 39 publications

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Indigestible mitochondria cause heartburn

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