The protective effect of interfering TLR9-IRF5 signaling pathway on the development of CVB3-induced myocarditis

Nie, Shu; Dong, Boqi; Gao, Shuang; Zhou, Yan; Lu, Weiyue; Fang, Mingli; Hua, Shucheng; Yu, Yongli; Wang, Liying

doi:10.1016/j.clim.2019.07.002

Cited by 9 publications

(9 citation statements)

References 50 publications

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“…The decrease of pathological changes is tightly associated with the inhibition of inflammatory cytokines and HMGB1 release ( Lai et al, 2016 ). More importantly, MS19 significantly improved the survival rate of mice in LPS-induced ALI model, which is similar with the previous animal results of MS19 in rescuing the mice from bacterial septic peritonitis, burn-induced systemic inflammation, and coxsackievirus B3 (CVB3)-induced myocarditis ( Gao et al, 2017 ; Xiao et al, 2017 ; Nie et al, 2019 ). Those data provided a supplemental experimental basis for the therapeutic applications in the treatment of numerous inflammatory diseases.…”

Section: Discussionsupporting

confidence: 87%

“…It was confirmed that MS19 could reduce the expression of IRF5 and inhibit the nuclear translocation of IRF5 in RAW264.7 cells, since the sequence of AAAG unit is in consensus with the DNA-binding site of IRF5 ( Gao et al, 2017 ). Moreover, MS19 also decreased the expression of IRF5 in the burn injury skin and the myocardial tissues of coxsackievirus B3-infected mice ( Xiao et al, 2017 ; Nie et al, 2019 ). However, there are still more inflammatory signaling pathways that are involved in the regulation of TLR-induced inflammation, such as the NF-κB and MAPK signaling.…”

Section: Introductionmentioning

confidence: 98%

“…In our previous study, an oligodeoxynucleotide (ODN) named as MS19, designed based on the sequence of human microsatellite DNA (MS DNA), with six AAAG repeated units. It could not only rescue mice from bacterial septic peritonitis ( Gao et al, 2017 ) but also attenuate the acute lung injury (ALI) and myocarditis in virus-infected mice ( Fang et al, 2011 ; Nie et al, 2019 ). It was confirmed that MS19 could reduce the expression of IRF5 and inhibit the nuclear translocation of IRF5 in RAW264.7 cells, since the sequence of AAAG unit is in consensus with the DNA-binding site of IRF5 ( Gao et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

Zhang

Wang

et al. 2022

Front. Microbiol.

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Acute lung injury (ALI) with uncontrolled inflammatory response has high morbidity and mortality rates in critically ill patients. Pathogen-associated molecular patterns (PAMPs) are involved in the development of uncontrolled inflammatory response injury and associated lethality. In this study, we investigated the inhibit effect of MS19, a microsatellite DNA-derived oligodeoxynucleotide (ODN) with AAAG repeats, on the inflammatory response induced by various PAMPs in vitro and in vivo. In parallel, a microsatellite DNA with AAAC repeats, named as MS19-C, was used as controls. We found that MS19 extensively inhibited the expression of inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α induced by various PAMPs stimulation, including DNA viruses, RNA viruses, bacterial components lipopolysaccharide (LPS), and curdlan, as well as the dsDNA and dsRNA mimics, in primed bone marrow-derived macrophage (BMDM). Other than various PAMPs, MS19 also demonstrated obvious effects on blocking the high mobility group box1 (HMGB1), a representative damage-associated-molecular pattern (DAMP), nuclear translocation and secretion. With the base substitution from G to C, MS19-C has been proved that it has lost the inhibitory effect. The inhibition is associated with nuclear factor kappa B (NF-κB) signaling but not the mitogen-activated protein kinase (MAPK) transduction. Moreover, MS19 capable of inhibiting the IL-6 and TNF-α production and blocking the HMGB1 nuclear translocation and secretion in LPS-stimulated cells was used to treat mice ALI induced by LPS in vivo. In the ALI mice model, MS19 significantly inhibited the weight loss and displayed the dramatic effect on lessening the ALI by reducing consolidation, hemorrhage, intra-alveolar edema in lungs of the mice. Meanwhile, MS19 could increase the survival rate of ALI by downregulating the inflammation cytokines HMGB1, TNF-a, and IL-6 production in the bronchoalveolar lavage fluid (BALF). The data suggest that MS19 might display its therapeutic role on ALI by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

Zhang

Wang

et al. 2022

Front. Microbiol.

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“…Therefore, clinically, investigations into the cytokine profile of FM patients can broaden our knowledge about the underlying pathophysiological process of FM and guide therapeutic decisions. 58 Activation of cytokine 'storm' can be triggered by various etiologies including pathogens such as viruses, 59 bacteria, 60 spirochete 61 , and fungi 62 (Table 1), which can initiate effects through receptors, like toll-like receptors (TLR). For example, leakage of intracellular components from damaged cardiomyocytes trigger an innate immune responses by activating TLR4.…”

Section: Pathophysiological Mechanisms Underlying Fmmentioning

confidence: 99%

Fulminant myocarditis: a comprehensive review from etiology to treatments and outcomes

Hang

Chen

Seubert

et al. 2020

Sig Transduct Target Ther

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Fulminant myocarditis (FM) is characterized by a rapid progressive decline in cardiac function and a high mortality rate. Since the first report of FM patients in the 1980s, several clinical trials and research studies have been published increasing our knowledge regarding FM. Currently, the diagnosis of FM depends on various techniques including electrocardiography, echocardiography, endomyocardial biopsy, and cardiac magnetic resonance. The development of mechanical circulation support (MCS) devices and progress in our understanding of the pathophysiological mechanisms underlying FM, treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach. The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm. This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology, pathophysiology, treatments, and outcomes.

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“…TLR 3, TLR 4 and TLR 9 activation after recognizing pathogen-associatedmolecular-patterns (PAMPs) during VMC was shown to worsen the severity of inflammation in CVB3-infected mouse hearts. In line, specific inhibition of TLR 3 and TLR 4 function by MiR-146a, an anti-TLR9 oligodeoxynucleotide, or Lupeol alleviated the CVB3-triggered cardiac inflammation, making TLR-specific therapy a possible option for VMC patients [43][44][45]. Secreted cytokines appear to be either beneficial or detrimental during viral myocarditis, depending on the cytokine, timing of secretion or administration, and secreted amount.…”

Section: Activation Of Innate Immune Systemmentioning

confidence: 92%

Virus-Host Interactions of Enteroviruses and Parvovirus B19 in Myocarditis

Peischard

Strutz‐Seebohm

et al. 2021

Cell Physiol Biochem

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Viral diseases are a major threat to modern society and the global health system. It is therefore of utter relevance to understand the way viruses affect the host as a basis to find new treatment solutions. The understanding of viral myocarditis (VMC) is incomplete and effective treatment options are lacking. This review will discuss the mechanism, effects, and treatment options of the most frequent myocarditis-causing viruses namely enteroviruses such as Coxsackievirus B3 (CVB3) and Parvovirus B19 (PVB19) on the human heart. Thereby, we focus on: 1. Viral entry: CVB3 use Coxsackievirus-Adenovirus-Receptor (CAR) and Decay Accelerating Factor (DAF) to enter cardiac myocytes while PVB19 use the receptor globoside (Gb4) to enter cardiac endothelial cells. 2. Immune system responses: The innate immune system mediated by activated cardiac toll-like receptors (TLRs) worsen inflammation in CVB3-infected mouse hearts. Different types of cells of the adaptive immune system are recruited to the site of inflammation that have either protective or adverse effects during VMC. 3. Autophagy: CVB3 evades autophagosomal degradation and misuses the autophasomal pathway for viral replication and release. 4. Viral replication sites: CVB3 promotes the formation of double membrane vesicles (DMVs), which it uses as replication sites. PVB19 uses the host cell nucleus as the replication site and uses the host cell DNA replication system. 5. Cell cycle manipulation: CVB3 attenuates the cell cycle at the G1/S phase, which promotes viral transcription and replication. PVB19 exerts cell cycle arrest in the S phase using its viral endonuclease activity. 6. Regulation of apoptosis: Enteroviruses prevent apoptosis during early stages of infection and promote cell death during later stages by using the viral proteases 2A and 3C, and viroporin 2B. PVB19 promotes apoptosis using the non-structural proteins NS1 and the 11 kDa protein. 7. Energy metabolism: Dysregulation of respiratory chain complex expression, activity and ROS production may be altered in CVB3- and PVB19-mediated myocarditis. 8. Ion channel modulation: CVB3-expression was indicated to alter calcium and potassium currents in Xenopus laevis oocytes and rodent cardiomyocytes. The phospholipase 2-like activity of PVB19 may alter several calcium, potassium and sodium channels. By understanding the general pathophysiological mechanisms of well-studied myocarditis-linked viruses, we might be provided with a guideline to handle other less-studied human viruses.

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The protective effect of interfering TLR9-IRF5 signaling pathway on the development of CVB3-induced myocarditis

Cited by 9 publications

References 50 publications

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

Fulminant myocarditis: a comprehensive review from etiology to treatments and outcomes

Virus-Host Interactions of Enteroviruses and Parvovirus B19 in Myocarditis

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