Myeloid Differentiation Factor-88 Plays a Crucial Role in the Pathogenesis of Coxsackievirus B3–Induced Myocarditis and Influences Type I Interferon Production

Fuse, Koichi; Chan, Grace; Liu, Youan; Gudgeon, Patrick; Husain, Mansoor; Chen, Manyin; Yeh, Wen-Chen; Akira, Shizuo; Liu, Peter P.

doi:10.1161/circulationaha.105.536433

Cited by 168 publications

(142 citation statements)

References 38 publications

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“…Using macrophages derived from MyD88 2/2 mice, we demonstrate that IFN-b gene expression was significantly enhanced in the absence of MyD88. This correlates gene induction and enhanced dimeric IRF3 following exposure to the ssRNA nonenveloped coxsackievirus B3, also a member of the Picornaviridae family of viruses (35). In this study, we also demonstrate that the downstream marker of JNK activation, namely PRDIV reporter gene activity, was not affected by MyD88.…”

Section: Discussionsupporting

confidence: 59%

Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-β and RANTES Production

Siednienko

Gajanayake

Fitzgerald

et al. 2011

The Journal of Immunology

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Toll-like receptors are a group of pattern-recognition receptors that play a crucial role in “danger” recognition and induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral dsRNA, resulting in the induction of the anti-viral molecule, IFN-β. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Previous studies have shown that the TLR adaptor, Mal/TIRAP, an activator of TLR4, inhibits TLR3-mediated IFN-β induction through a mechanism involving IRF7. In this study, we sought to investigate whether the TLR adaptor, MyD88, an activator of all TLRs except TLR3, has the ability to modulate TLR3 signaling. Although MyD88 does not significantly affect TLR3 ligand-induced TNF-α induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN-β and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKKε-, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN-β induction. The present study shows that while MyD88 activates all TLRs except TLR3, MyD88 also functions as a negative regulator of TLR3. Thus, MyD88 is essential in restricting TLR3 signaling, thereby protecting the host from unwanted immunopathologies associated with the excessive production of IFN-β. Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKKε-mediated induction of IRF3 and concomitant IFN-β and RANTES production.

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Section: Discussionsupporting

confidence: 59%

Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-β and RANTES Production

Siednienko

Gajanayake

Fitzgerald

et al. 2011

The Journal of Immunology

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“…2B) [19]. In this model, virus replicates at relatively low levels in the heart during acute myocarditis (10 2 -10 4 PFU) compared with other CVB3-induced models (10 7 -10 9 PFU) [8][9][10][11]18,19]. By day 14 pi, infectious virus is cleared from the heart and does not reactivate during chronic myocarditis [6,15].…”

Section: Introductionmentioning

confidence: 93%

“…Murine models fall into two basic categories: acute cardiac inflammation and sudden death induced by direct viral damage (where nearly 70% of animals die at day 4 to 7 after infection) [8][9][10][11], or inflammation triggered by adjuvant and cardiac myosin or virus and cardiac myosin (heart-passaged virus) resulting in acute myocarditis with no deaths that progresses to chronic heart disease and DCM [5,6,[12][13][14][15]. In this article, we describe a model of autoimmune myocarditis and DCM induced by inoculation with heart-passaged CVB3 [7,15].…”

Section: Introductionmentioning

confidence: 99%

Coxsackievirus-induced myocarditis in mice: A model of autoimmune disease for studying immunotoxicity

Fairweather¹,

Rose²

2007

Methods

179

185

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Excellent animal models are available of virus-induced and autoimmune heart disease that are remarkably similar to human disease. Developing good animal models for heart disease is crucial because cardiovascular disease is now the leading cause of death in the United States and is estimated to be the leading cause of death in the world by the year 2020. A significant proportion of heart disease in Western populations is associated with inflammation. Myocarditis, or inflammation of the heart muscle, is the major cause of sudden death in young adults. Although most individuals recover from acute myocarditis, genetically susceptible individuals may go on to develop chronic myocarditis and dilated cardiomyopathy (DCM) resulting in congestive heart failure. In this article, we describe a model of autoimmune myocarditis and DCM induced by inoculation with heart-passaged coxsackievirus B3 (CVB3). Intraperitoneal inoculation of susceptible mice with CVB3 induces acute cardiac inflammation from days 7 to 14 post infection (pi) that progresses to chronic myocarditis and DCM from day 28 to at least 56 pi. The model of CVB3-induced myocarditis presented here allows dissection of the contribution of viral infection and xenobiotics on immune dysregulation and inflammation in the heart. An improved understanding of the interaction between environmental exposures and the development of heart disease represents a clear challenge for immunotoxicologists.

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“…These comprised the transcriptional up-regulation of Tolllike receptors as well as the induction of IFN type I-dependent gene expression. Downstream of TLR signaling, the adapter protein MyD88 is critical in different types of inflammatory cardiomyopathy (24,25). Ablation of MyD88 modulated our phenotype by attenuating the excessive gain in heart weight; however, it did not prevent heart failure.…”

Section: Role Of Chemokines Cytokines Adhesion Molecules and Myd88mentioning

confidence: 99%

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Maier

Schips²,

Wietelmann³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

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Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b + cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.transcription factors | transgenic mice

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Myeloid Differentiation Factor-88 Plays a Crucial Role in the Pathogenesis of Coxsackievirus B3–Induced Myocarditis and Influences Type I Interferon Production

Cited by 168 publications

References 38 publications

Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-β and RANTES Production

Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-β and RANTES Production

Coxsackievirus-induced myocarditis in mice: A model of autoimmune disease for studying immunotoxicity

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

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