TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo

Boehm, Olaf; Knuefermann, Pascal; Plueck, Johannes; Schwederski, Markus; Ehrentraut, Heidi; Kebir, Sied; Lohner, Ralph; Velten, Markus; Morath, Siegfried; Koch, Alexander; Zacharowski, Kai; Grohé, Christian; Hoeft, Andreas; Baumgarten, Georg; Meyer, Rainer

doi:10.1186/1476-9255-10-33

Cited by 8 publications

(6 citation statements)

References 35 publications

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“…Moreover, TLR2 deficiency preserved the cardiac structure and ventricular function after acute myocardial infarction (17). In experimental mice models, TLR2 deficiency attenuated Staphylococcus aureus-or doxorubicininduced cardiac dysfunction (18,19). On similar lines, TLR2 deficiency reduces the severity of atherosclerosis in low-density lipoprotein receptordeficient mice (20).…”

Section: Introductionmentioning

confidence: 95%

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Spurthi

Sarikhani

Mishra

et al. 2018

Journal of Biological Chemistry

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Toll-like receptors (TLRs) are a family of patternrecognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied agingassociated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8-and 12-months-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-monthsold TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophyrelated ubiquitin ligases MuRF-1 and Atrogin-1. Mechanistically, TLR2-deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor forkhead box protein O1 (FoxO1), and, in turn, to elevated expression of FoxO target genes involved in regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling, while improving the contractile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice.

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Section: Introductionmentioning

confidence: 95%

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Spurthi

Sarikhani

Mishra

et al. 2018

Journal of Biological Chemistry

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“…Inflammation is pivotal for the development of heart failure, and an unrestricted inflammatory response is associated with worse prognosis after MI [6,7]. Furthermore, excessive increases in inflammatory mediators, e.g., cytokines, have been shown to induce myocardial injury, including impaired cardiomyocyte contractility and excessive myocardial remodeling [8][9][10][11]. Myocardial reperfusion after ischemia generates an imbalance between reactive oxygen species (ROS) and the capacity of cells to defend against them, leading to increased ROS generation.…”

Section: Introductionmentioning

confidence: 99%

DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice

Habicht

Mohsen

Eichhorn

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. Methods. C57BL/6N mice were placed on DHA or control diets (CD) beginning 7 d prior to 60 min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14 d. Results. DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-α (PPAR-α) (2.3±0.4 CD vs. 1.4±0.3 DHA) after LAD occlusion. Furthermore, TNF-α (4.0±0.6 CD vs. 1.5±0.2 DHA), IL-1β (60.7±7.0 CD vs. 11.6±1.9 DHA), and IL-10 (223.8±62.1 CD vs. 135.5±38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72 h reperfusion. These changes were accompanied by a less prominent switch in α/β myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6 h: 32.8±11.5 CD vs. 78.8±13.6 DHA) but terminated earlier (CCL2 72 h: 39.5±7.8 CD vs. 8.2±1.9 DHA; CCL3 72 h: 794.3±270.9 CD vs. 258.2±57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14 d: 17.6±2.6 CD vs. 31.4±1.5 DHA). Conclusion. Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-α downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or α- to β-MHC isoform switch.

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“…Due to matters of comparability, we decided to also perform hemodynamic measurements and tissue harvesting 6 h after TLR ligand application. Recent reports revealed that application of ultrapure LTA seems to be a less potent stimulus for cardiac inflammation, depression and vascular contractility compared to LPS [ 5 , 13 ]. NFκB activation and pro-inflammatory cytokine mRNA expression and protein secretion reached their maximum 2–4 h after LTA stimulation and returned to baseline after 6 h. This observation is in line with our results and might explain why only modest alteration of cytokine protein expression was detectable after LTA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) recognizing pathogen associated molecular patterns such as gram-positive (TLR1, -2, -6) and gram-negative virulence factors (TLR4) as well as bacterial DNA (TLR9). These bacterial TLR ligands may contribute to the pathogenesis of sepsis-induced myocardial inflammation and dysfunction [ 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

Tlr4 Deficiency Protects against Cardiac Pressure Overload Induced Hyperinflammation

Ehrentraut

Boehm

et al. 2015

PLoS ONE

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Transverse aortic constriction provokes a pro-inflammatory reaction and results in cardiac hypertrophy. Endogenous ligands contribute to cardiac hypertrophy via toll-like receptor (TLR)-4 binding. A lack of TLR4 signaling diminishes hypertrophy and inflammation. Wild type mice undergoing aortic constriction respond to a lipopolysaccharide second-hit stimulus with hyperinflammation. The objective of this study was to assess whether other second-hit challenges utilizing TLR ligands provoke a comparable inflammatory reaction, and to find out whether this response is absent in TLR4 deficient mice. Assuming that cardiac stress alters the expression of pattern recognition receptors we analyzed the effects of transverse aortic constriction and second-hit virulence factor treatment on TLR expression, as well as cytokine regulation. Wild type and Tlr4 -/- mice were subjected to three days of TAC and subsequently confronted with gram-positive TLR2 ligand lipoteichoic acid (LTA, 15mg/g bodyweight) or synthetic CpG-oligodesoxynucleotide 1668 thioate (20 nmol/kg bodyweight, 30 min after D-galactosamin desensitization) signaling via TLR9. Hemodynamic measurements and organ preservation were performed 6 h after stimulation. Indeed, the study revealed a robust enhancement of LTA induced pattern recognition receptor and cytokine mRNA expression and a LTA-dependent reduction of hemodynamic pressure in TAC wild type mice. Second-Hit treatment with CpG-ODNs led to similar results. However, second-hit effects were abolished in Tlr4 -/- mice. In total, these data indicate for the first time that cardiac stress increases the inflammatory response towards both, gram-negative and gram-positive, TLR ligands as well as bacterial DNA. The decrease of the inflammatory response upon TLR2 and -9 ligand challenge in TAC Tlr4 -/- mice demonstrates that a lack of TLR4 signaling does not only prevent left ventricular hypertrophy but also protects the mice from a cardiac stress induced hyperinflammatory reaction.

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TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo

Cited by 8 publications

References 35 publications

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice

Tlr4 Deficiency Protects against Cardiac Pressure Overload Induced Hyperinflammation

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