Thrombomodulin's lectin-like domain reduces myocardial damage by interfering with HMGB1-mediated TLR2 signalling

Herzog, Christine; Lorenz, Anika; Gillmann, H; Chowdhury, Arpita; Larmann, Jan; Harendza, Thomas; Echtermeyer, Frank; Müller, Martin; Schmitz, Martina; Stypmann, Jörg; Seidler, Daniela G.; Damm, Martin; Stehr, Sebastian; Koch, Thea; Wollert, Kai C.; Conway, Edward M.; Theilmeier, Gregor

doi:10.1093/cvr/cvt275

Cited by 48 publications

(40 citation statements)

References 34 publications

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“…Knockout of TLR4 in vitro or in vivo decreases HMGB1-induced tissue injury (Laird et al, 2014; Yang et al, 2013e; Ye et al, 2013a), cell migration and adhesion (Bauer et al, 2013) (Furlani et al, 2012; Wang et al, 2013m), angiogenesis (Lin et al, 2011), and the inflammation (Lv et al, 2009; Tadie et al, 2012b; Zong et al, 2013) and immunity responses (Apetoh et al, 2007). In addition to TLR4, TLR2 is required for tissue injury (Herzog et al, 2014; Kim et al, 2012h; Kruger et al, 2010; Leemans et al, 2009; Li et al, 2009), cell migration and adhesion (Furlani et al, 2012), inflammation (Park et al, 2006; Yu et al, 2006b), and self-renewal of stem cells (Conti et al, 2013). TLR9 is generally responsible for HMGB1-DNA complex-induced nucleotide immunity and RAGE can enhance this process (Bamboat et al, 2010; Hirata et al, 2013; Ivanov et al, 2007; Tian et al, 2007; Yanai et al, 2009).…”

Section: Hmgb1 Receptors (Figure 7)mentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

822

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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Section: Hmgb1 Receptors (Figure 7)mentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

822

828

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“…Although high mobility group box-1 (HMGB1) has been suggested as important cardiomyocyte-derived alarmin[3], [4]; the identity of the key primary stimulus that may trigger the inflammatory reaction following infarction remains unknown. Using a combination of in vivo and in vitro approaches, Lugrin and co-workers[5] demonstrated that necrotic cardiomyocytes release Interleukin (IL)-1α, a key early damage signal that activates the abundant fibroblasts in the myocardium, promoting their pro-inflammatory activation through MyD88-dependent, toll like receptor (TLR)-independent signaling (Figure 1).…”

Section: Activation Of Pro-inflammatory Cascades Following Cardiac Inmentioning

confidence: 99%

Inflammation in cardiac injury, repair and regeneration

Frangogiannis

2015

Current Opinion in Cardiology

166

133

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Purpose of the review Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. Recent findings Recently published studies have identified Interleukin (IL)-1α and RNA released by necrotic cardiomyocytes as key danger signals that trigger the inflammatory response following infarction. IL-1 promotes activation of a pro-inflammatory phenotype in leukocytes and fibroblasts, and delays myofibroblast transdifferentiation. Inhibitory lymphocytes play a crucial role in negative regulation of the post-infarction inflammatory response by modulating macrophage and fibroblast phenotype. Cardiac macrophages exhibit significant heterogeneity and phenotypic plasticity and may orchestrate the reparative response following infarction. In neonatal mice, resident embryonic macrophage subpopulations may promote a regenerative response. In contrast, in adult animals replacement of resident macrophage populations with monocyte-derived macrophages may induce inflammation while inhibiting cardiac regeneration. These exciting observations highlight the crucial role of macrophages in cardiac injury and repair, but should be interpreted with caution considering the limitations of murine models of neonatal myocardial injury. Summary Design of novel strategies to reduce cardiac injury, improve repair and promote regeneration is dependent on understanding of the cell biology of the inflammatory response.

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“…Therefore, HMGB1 has been recognized as an important pro-inflammatory mediator and is important in initiating and amplifying the inflammatory response (9–12). In addition, it has been reported that the HMGB1-triggered inflammatory response is crucial in myocardial I/R injury since a decrease in HMGB1 expression and release could significantly inhibit the inflammatory response and ameliorate I/R-induced myocardial injury (11,33). Therefore, inhibition of the HMGB1-mediated inflammatory signaling pathway may be a promising therapeutic strategy for myocardial I/R injury.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies demonstrated that extracellular HMGB1 is a potent pro-inflammatory mediator (9,10), and is important in triggering the inflammatory response during myocardial I/R (11,12). Furthermore, it has been reported that HMGB1 exerts its pro-inflammatory effects via its specific receptors, which mainly include a receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)-2 and TLR-4 (13).…”

Section: Introductionmentioning

confidence: 99%

Picroside II protects myocardium from ischemia/reperfusion-induced injury through inhibition of the inflammatory response

Meiqing

et al. 2016

Experimental and Therapeutic Medicine

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The inflammatory response is important in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Picroside II, the primary active constituent of Picrorhizae, has been reported to protect the myocardium from I/R-induced injury, however, the exact mechanism underlying these protective effects remains unclear. The aim of the present study was to investigate the mechanism underlying the protective effects of picroside II on I/R-induced myocardial injury. Adult male Sprague-Dawley rats underwent 1 h left coronary artery occlusion followed by 3 h reperfusion. Picroside II was administered (10 mg/kg) via the tail vein 30 min prior to left coronary artery occlusion. The results revealed that pretreatment of picroside II could significantly alleviate I/R-induced myocardial injury concomitantly with a decrease in inflammatory factor production. In addition, picroside II was also able to decrease high mobility group box 1 (HMGB1) expression, and release and downregulate the expression of the receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2 and TLR-4. Furthermore, picroside II was able to inhibit nuclear factor-κB (NF-κB) activation. The results indicated that the protective effect of picroside II on I/R-induced myocardial injury was associated, at least partly, with inhibition of the inflammatory response by suppressing the HMGB1-RAGE/TLR-2/TLR-4-NF-κB signaling pathway.

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Thrombomodulin's lectin-like domain reduces myocardial damage by interfering with HMGB1-mediated TLR2 signalling

Abstract: The LLD of TM suppresses HMGB1-induced and TLR2-mediated myocardial reperfusion injury and apoptosis in vitro and in vivo.

Cited by 48 publications

References 34 publications

HMGB1 in health and disease

HMGB1 in health and disease

Inflammation in cardiac injury, repair and regeneration

Picroside II protects myocardium from ischemia/reperfusion-induced injury through inhibition of the inflammatory response

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