Interleukin-6–Deficient Mice Resist Development of Autoimmune Myocarditis Associated With Impaired Upregulation of Complement C3

Eriksson, Urs; Kurrer, Michael; Schmitz, Nicole; Marsch, Stephan; Fontana, Adriano; Eugster, Hans-Pietro; Köpf, Manfred

doi:10.1161/01.cir.0000043802.38699.66

Cited by 132 publications

(132 citation statements)

References 36 publications

(50 reference statements)

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“…In this context, it has been shown recently, that IL-6, which is essential for the induction of Th17 T cells (8), and IL-23-promoting Th17 expansion are both critical for EAM development (12,13). Our data prove the direct pathogenic role of IL-17 in EAM development, because IL-17 depletion prevents EAM development.…”

Section: Discussionsupporting

confidence: 71%

“…Mice were immunized with 150 g of the MyHC-␣ (MyHC-␣ 614 -634 ) Ac-SLKLMATLFSTYASAD-OH emulsified 1:1 in PBS/CFA (1 mg/ml, H37Ra; Difco) as described (8).…”

Section: Immunization Protocolsmentioning

confidence: 99%

“…EAM can be induced in susceptible mouse strains by immunization with self-peptides derived from the myosin ␣ H chain (MyHC-␣) together with a strong adjuvant (7,8), or by injection of activated, MyHC-␣-loaded dendritic cells (9,10). In wild-type mice, disease severity peaks 2-3 wk after immunization.…”

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confidence: 99%

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CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

Valaperti

Marty

Kania

et al. 2008

The Journal of Immunology

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Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after α-myosin H chain peptide (MyHC-α)/CFA immunization and largely resolving thereafter. In IFN-γR−/− mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-γR−/− mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b+ monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b+ monocytes suppressed MyHC-α-specific Th17 T cell responses IFN-γ-dependently in vitro. In vivo, injection of IFN-γR+/+CD11b+, but not IFN-γR−/−CD11b+, monocytes, suppressed MyHC-α-specific T cells, and abrogated the progressive disease course in IFN-γR−/− mice. Finally, coinjection of MyHC-α-specific, but not OVA-transgenic, IFN-γ-releasing CD4+ Th1 T cell lines, together with MyHC-α-specific Th17 T cells protected RAG2−/− mice from EAM. In conclusion, CD11b+ monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-γ-dependent negative feedback loop confining disease progression.

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Section: Discussionsupporting

confidence: 71%

“…Mice were immunized with 150 g of the MyHC-␣ (MyHC-␣ 614 -634 ) Ac-SLKLMATLFSTYASAD-OH emulsified 1:1 in PBS/CFA (1 mg/ml, H37Ra; Difco) as described (8).…”

Section: Immunization Protocolsmentioning

confidence: 99%

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CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

Valaperti

Marty

Kania

et al. 2008

The Journal of Immunology

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129

120

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“…Mice were inoculated with 100 mg of MyHC-a (MyHC-a 614-629; Ac-SLKLMATLFSTYASAD-OH), emulsified at a 1:1 ratio in PBS/CFA at days 0 and 7 as previously described [48]. At different time points, the mice were anaesthetized with pento- Figure 6.…”

Section: Induction Of Myocarditismentioning

confidence: 99%

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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High-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been implicated in cardiovascular diseases. Dilated cardiomyopathy (DCM), one of the leading causes of heart failure, is often caused by coxsackievirus B3-triggered myocarditis and promoted by the post-infectious autoimmune process. Th17 cells, a novel CD4 1 T subset, may be important in the pathogenesis of autoimmune myocarditis. In the present study, we attempted to block HMGB1 function with a monoclonal antibody specific for HMGB1 B box and investigated the effects of the blockade on Th17 cells and experimental autoimmune myocarditis (EAM). After induction of EAM, HMGB1 protein levels were significantly elevated both in the heart and blood. Administration of an anti-HMGB1 B box mAb attenuated cardiac pathological changes and reduced the number of infiltrating inflammatory cells in the heart during EAM. These protective effects of HMGB1 blockade correlated with a reduced number of Th17 cells in local tissues and lower levels of IL-17 in the serum. Furthermore, in vitro, studies demonstrated that HMGB1 promoted Th17-cell expansion. Therefore, we speculate that HMGB1 blockade ameliorates cardiac pathological changes in EAM by suppressing Th17 cells.Key words: Dilated cardiomyopathy . Experimental myocarditis . HMGB1 . Th17 cells IntroductionHigh-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been functionally characterized as an alarmin or damage-associated molecular pattern (DAMP) [1,2]. It is constitutively expressed in quiescent cells and stored in the nucleus [3]. HMGB1 is one of the most evolutionarily conserved proteins in eukaryotes, with 100% identity between mice and rats, and 99% identity between rodents and humans [3].HMGB1 has been shown to be involved in both infectious and non-infectious inflammatory disease [2,4]. HMGB1 is released into the extracellular milieu during cell apoptosis/death [5], and by macrophages and monocytes in response to cellular stress or injury [6]. HMGB1 binds to the endogenous receptor for advanced glycation endproducts [7], exogenous toll-like receptor 2/4/9 (TLR2/4/9) [8,9], and CD24/Siglec-10 [10], and induces the expression of proinammatory cytokines, chemokines, and adhesion molecules [3,6]. Although, HMGB1 was initially 3586thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].Dilated cardiomyopathy (DCM) is one of the leading causes of severe heart failure and the most common indication for heart transplantation. DCM is often caused by coxsackievirus B3-triggered myocarditis [21]. Experimental autoimmune myocarditis (EAM) is a mouse model of postinfectious myocarditis, characterized by inflammatory infiltration of the myocardium and cardiac myocyte ne...

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“…A number of proinflammatory cytokines, including IL-1b, IL-6, IL-12, TNF-a, and GM-CSF, have been shown to contribute to the development of autoimmune myocarditis in animal models and human cases (8)(9)(10)(11)(12)(13). EAM is a CD4 + T cell-mediated disease (7,14), and activation of self-Ag-loaded dendritic cells (DCs) is critical for expansion of autoreactive CD4 + T cells.…”

mentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Tajiri

Imanaka‐Yoshida

Matsubara

et al. 2012

The Journal of Immunology

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Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4+ T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.

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Interleukin-6–Deficient Mice Resist Development of Autoimmune Myocarditis Associated With Impaired Upregulation of Complement C3

Cited by 132 publications

References 36 publications

CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

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