Differential Interferon Responses Enhance Viral Epitope Generation by Myocardial Immunoproteasomes in Murine Enterovirus Myocarditis

Jäkel, Sandra; Kuckelkorn, Ulrike; Szalay, Gudrun; Plötz, Michael; Textoris-Taube, Kathrin; Opitz, Erich; Klingel, Karin; Stevanović, Stefan; Kandolf, Reinhard; Kotsch, Katja; Stangl, Karl; Kloetzel, Peter M.; Voigt, Antje

doi:10.2353/ajpath.2009.090033

Cited by 38 publications

(72 citation statements)

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“…In addition to severe maturation/DC activation defects in CVB3-challenged A.BY/SnJ mice, limitation of the CVB3-protein containing antigenic pool may further impair T-cell priming in this host. In fact, CD8 1 T-cell responses, which exert their antigenic potential primarily by IFN-g release [6], are impaired in acute myocarditis in A.BY/SnJ mice [4]. These data highlight the effect of DC function on the induction of specific anti-viral adaptive immune responses for efficient virus clearance in murine enterovirus myocarditis.…”

Section: Ubiquitinylation/dalis Accumulation/isgylation In Dcs In Cvbmentioning

confidence: 82%

“…Mice CVB3 (cardiotropic Nancy strain) infection was performed as previously described [4]. Mice were kept at the animal facilities of the Charité University Medical Center.…”

Section: Methodsmentioning

confidence: 99%

“…3A and B). Thus, once optimal expression levels of cytokines/chemokines, MHC molecules and co-stimulatory molecules were achieved in C57BL/6 mice, DALISs were dissolved presumably resulting in MHC-I antigen processing by the proteasome [4,29,31]. In contrast to the findings in the resistant host, DALIS maintenance was detected in DCs from A.BY/SnJ mice also at later stages of maturation (high detection levels at 48 h p.i.…”

Section: Ubiquitinylation/dalis Accumulation/isgylation In Dcs In Cvbmentioning

confidence: 96%

“…Immune surveillance mechanisms involving type I IFN responses [4,8,9], efficient antigen processing of CVB3 epitopes by cardiac immunoproteasomes [4] and potent CD8 1 T-cell responses [6] are crucial determinants in the disease progress in CVB3 myocarditis. Initiation of these antiviral immune responses strongly relies on the function of professional APCs.…”

Section: Short Communicationmentioning

confidence: 99%

“…Ongoing research focuses on the delineation of host determinants that identify patients at risk for the development of chronic disease. The murine model of ongoing CVB3-myocarditis properly mimics human disease progression [3][4][5][6][7]: upon CVB3 infection so-called resistant C57BL/6 mice eliminate the virus following acute myocarditis. In contrast, MHC-matched, immunocompetent A.BY/SnJ mice develop ongoing chronic myocarditis with chronic virus persistence [3,6].…”

Section: Introductionmentioning

confidence: 99%

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Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

et al. 2011

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Coxsackievirus B3 (CVB3)‐infection is a frequent cause of acute myocarditis, which may result in chronic myocarditis and virus persistence. Investigation of the initial immune responses to CVB3 may shed light on the mechanisms that contribute to ongoing disease. DCs, as key professional APCs, were investigated in two MHC‐matched hosts: while C57BL/6 mice are resistant to chronic CVB3‐myocarditis, the A.BY/SnJ mouse strain exhibits susceptibility. DC maturation and activation were critically impaired in A.BY/SnJ mice, as reflected by the failure of DCs to induce co‐stimulatory molecules and cytokine/chemokine responses. MHC class I‐restricted antigen presentation via the cross‐presentation pathway was also affected in DCs from A.BY/SnJ mice. DC maturation involves the accumulation of DC aggresome‐like induced structures (DALISs) and the transient storage of defective ribosomal products (DRiPs). DCs from A.BY/SnJ mice showed permanent DALIS accumulation; the detection of poly‐ubiquitinylated CVB3 proteins in these DALISs suggested a limitation in the MHC class I antigenic supply in this host. In conclusion, ongoing chronic disease in A.BY/SnJ mice due to a failure to clear the virus may be attributed to defects in DC maturation/activation and DC MHC class I antigen processing.

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Section: Ubiquitinylation/dalis Accumulation/isgylation In Dcs In Cvbmentioning

confidence: 82%

“…Mice CVB3 (cardiotropic Nancy strain) infection was performed as previously described [4]. Mice were kept at the animal facilities of the Charité University Medical Center.…”

Section: Methodsmentioning

confidence: 99%

Section: Ubiquitinylation/dalis Accumulation/isgylation In Dcs In Cvbmentioning

confidence: 96%

Section: Short Communicationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

et al. 2011

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The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3

et al. 2015

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Cardiomyocyte death as a result of viral infection is an excellent model for dissecting the inflammatory stress response that occurs in heart tissue. We reported earlier that a specific proteasome isoform, the immunoproteasome, prevents exacerbation of coxsackievirus B3 (CVB3)-induced myocardial destruction and preserves cell vitality in heart tissue inflammation. Following the aim to decipher molecular targets of immunoproteasome-dependent proteolysis, we investigated the function and regulation of the soluble PRR Pentraxin3 (PTX3). We show that the ablation of PTX3 in mice aggravated CVB3-triggered inflammatory injury of heart tissue, without having any significant effect on viral titers. Thus, there might be a role of PTX3 in preventing damageassociated molecular pattern-induced cell death. We found that the catalytic activity of the immunoproteasome subunit LMP7 regulates the timely availability of factors controlling PTX3 production. We report on immunoproteasome-dependent alteration of ERK1/2 and p38MAPKs, which were both found to be involved in PTX3 expression control. Our finding of a cardioprotective function of immunoproteasome-dependent PTX3 expression revealed a crucial mechanism of the stress-induced damage response in myocardial inflammation. In addition to antigen presentation and cytokine production, proteolysis by the immunoproteasome can also regulate the innate immune response during viral infection.Keywords: Infection r Inflammation r Innate immunity r Myocarditis r Pentraxin3 r Proteasome r Stress response r Virus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe myocardium can be injured by various pathophysiological processes. Myocarditis is an excellent model of heart muscle Correspondence: Dr. Antje Voigt e-mail: antje.voigt@charite.de injury for dissecting processes of the heart stress response to inflammation. In developed countries, myocarditis most commonly results from a virus infection, often by coxsackievirus B3 (CVB3) and adenoviruses. Fulminant injury of the heart muscle in * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 620Anna Paeschke et al. Eur. J. Immunol. 2016. 46: 619-633 viral myocarditis is attributed to both, direct virus-mediated cytotoxic effects and destruction of the heart muscle by the immune system [1,2]. The balance of intrinsic and innate immune mechanisms determines whether there is repair of the heart muscle or progression to chronic inflammation. This process involves the engagement of pattern recognition receptors (PRRs) either with pathogen-associated molecular patterns (PAMPs) such as viral RNA, or, upon the release of endogenous material, with damageassociated molecular patterns (DAMPs) [3]. Our knowledge on disease course in patients comes mainly from the mouse model of CVB3 myocarditis. Cardiotropic CVB3 infects mice and replicates to high titers, causing acute myocarditis (ACM) that faithfully mirrors...

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Pathophysiology and Mechanisms of Fulminant Myocarditis

Chen

Wang

2022

Fulminant Myocarditis

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Differential Interferon Responses Enhance Viral Epitope Generation by Myocardial Immunoproteasomes in Murine Enterovirus Myocarditis

Abstract: Murine models of coxsackievirus B3 (CVB3)-Myocarditis is often induced by cardiotropic viruses: in about 20% of patients, viral myocarditis leads to its sequela dilated cardiomyopathy, which is linked to chronic inflammation and persistence of cardiotropic viruses.

Cited by 38 publications

References 47 publications

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3

Pathophysiology and Mechanisms of Fulminant Myocarditis

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