Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

Abston, Eric; Coronado, Michael; Bucek, Adriana; Bedja, Djahida; Shin, Jaewook; Kim, Joseph B.; Kim, Eunyong; Gabrielson, Kathleen L.; Georgakopoulos, Dimitrios; Mitzner, Wayne; Fairweather, DeLisa

doi:10.1155/2012/129486

Cited by 90 publications

(106 citation statements)

References 34 publications

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“…Hearts were fixed in 10% buffered formalin and stained with hematoxylin and eosin to assess inflammatory cells or Masson's trichrome to detect collagen deposition. Myocarditis was assessed as the percentage of the heart section (i.e., ventricles) with hematoxylin staining, necrosis, and/or fibrosis compared with the overall size of the heart section at low power (ϫ25 magnification) using a microscope eyepiece grid, as has been done previously (1,2,11,18). Sections were scored by at least two individuals blinded to the treatment group.…”

Section: Methodsmentioning

confidence: 99%

“…TLR3 polymorphisms in myocarditis patients were recently found to be associated with an increased susceptibility to enteroviral myocarditis and DCM (30), suggesting that TLR3 may be important in protecting against the progression from myocarditis to iDCM. Recently, we showed that TLR3-deficient mice develop a T helper (Th)2-skewed immune response during acute CVB3 myocarditis and that an IL-4-driven Th2 response has less severe consequences than an IL-33-driven Th2 response on cardiac function (1,2). In this study, we further examined the mechanisms involved in protection mediated by TLR3 in the progression from myocarditis to iDCM.…”

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confidence: 97%

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TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Abston

Coronado

Bucek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute ( P = 5.9 × 10−9) and chronic ( P = 6.0 × 10−7) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 ( P = 0.03), IL-10 ( P = 0.008), IL-13 ( P = 0.002), and TGF-β1 ( P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3+ T cells ( P = 0.005) and Tim-3+ macrophages ( P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 97%

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Abston

Coronado

Bucek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…47 Mouse studies have shown that a deficiency of either TLR3 or its adaptor, TRIF, is associated with an increase in levels of virus and mortality after CVB3 or CVB4 infection. [48][49][50] Interestingly, type I IFNs (IFN-a and IFN-b), but not type II IFN (IFN-g), are required for the innate immune response to CVB3. 51 IFN-a and IFN-b are expressed at low levels by various cells but are induced in virally infected cells, such as CFs and cardiomyocytes in the heart.…”

Section: Par1 Modulation Of Tlr3 and Tlr4 Signaling In Cfsmentioning

confidence: 99%

Multiple roles of the coagulation protease cascade during virus infection

Antoniak

Mackman

2014

Blood

194

205

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The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.

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“…Although the virus is directly responsible for some organ injury, the majority of the injury is caused by the host inflammatory response to the virus (46). TLR3 or TRIF deficiency is associated with increased viral titers and a higher mortality after infection with CVB3 or CVB4 (47)(48)(49). Type I IFN signaling, but not type II IFN signaling, is required for an innate immune response to CVB3 infection (50).…”

Section: Introductionmentioning

confidence: 99%

PAR-1 contributes to the innate immune response during viral infection

Antoniak¹,

Owens²,

Baunacke³

et al. 2013

J. Clin. Invest.

138

227

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Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1 -/-mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1 +/+ mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1 -/-mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1 +/+ mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.

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Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

Cited by 90 publications

References 34 publications

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Multiple roles of the coagulation protease cascade during virus infection

PAR-1 contributes to the innate immune response during viral infection

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