Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis

Eriksson, Urs; Kurrer, Michael; Sonderegger, Ivo; Iezzi, Giovanna; Tafuri, Agostino; Hunziker, Lukas; Suzuki, Shinobu; Bachmaier, Kurt; Bingisser, Roland; Penninger, Josef; Köpf, Manfred

doi:10.1084/jem.20021788

Cited by 142 publications

(105 citation statements)

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“…Furthermore chronic, systemic administration of IL‐1 together with 6‐OHDA increases dopaminergic neuron loss and the number of MHC II‐positive cells (Pott Godoy et al, 2008). These data suggest that IL‐1β has a role in regulating MHC II responses after dopaminergic toxic insults, and mice null for the IL‐1 receptor 1 cannot activate CD4 + T‐cells (Eriksson et al, 2003). The IL‐1 β is probably derived from infiltrating MHC II‐monocytes.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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“…We previously reported that Tlr4 mutant C3H/HeJ mice are resistant to development of EAM (45). Furthermore, IL-1 type 1 receptor signaling on DCs is critical for autoimmune myocarditis development (11). MyD88 is a crucial common adaptor molecule that mediates both TLRs and IL-1 type 1 receptor activation (46,47), and MyD88 signaling in DCs is critical for the induction of EAM (16).…”

Section: Discussionmentioning

confidence: 99%

“…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. Activation of TLRs and IL-1 type 1 receptor and their common downstream signaling adaptor molecule, MyD88, in self-Ag-presenting DCs is also critical for the development of EAM (11,15,16). Compared with inhibition of a single cytokine, a more effective treatment might be inhibition of various signaling pathways to induce production of cytokines through both innate and adaptive immunity.…”

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confidence: 99%

“…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.…”

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confidence: 99%

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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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“…Myocarditis severity was evaluated blinded by a clinical pathologist on a semiquantitative scale using grades from 0 to 4 as described previously [10] (0: no inflammatory infiltrates; 1: small foci of inflammatory cells between cardiomyocytes; 2: larger foci of >100 inflammatory cells; 3: >10 % of a cross-section involved; 4: >30% of a cross-section involved). For immunohistochemistry and immunofluorescence, OTC-embedded frozen hearts were fixed in acetone and then processed for antibody staining according to standard protocols.…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

et al. 2015

Self Cite

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Experimental autoimmune myocarditis (EAM) is a CD4 + T-cell-mediated model of human inflammatory dilated cardiomyopathies.Heart-specific CD4 + T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV−/− K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with α-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV−/− K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4 + T cells and in expression of IFN-γ, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-γ neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-γ to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis. Keywords: CD4 + T cells Experimental autoimmune myocarditis (EAM) Endothelial antigen presentation Interferon-γ MHC class IIAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Hans Acha-Orbea e-mail: hans.acha-orbea@unil.ch C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 656-664 Immunomodulation 657 IntroductionInflammatory dilated cardiomyopathy is a common cause of heart failure in young patients and often results from myocarditis in predisposed individuals [1]. CD4 + T-cell-mediated experimental autoimmune myocarditis (EAM) is a model for inflammatory heart disease and is induced in mice either by immunization with α-myosin heavy chain (α-MyHC) derived peptides emulsified in CFA [2][3][4] or by vaccination with α-MyHC-loaded activated dendritic cells (DCs) [5]. Typically, both Th1 and Th17 cells are induced during the course of EAM. It is assumed that both of these subsets mediate myocarditis as mice deficient in either interleukin 17 (IL-17) or interferon γ (IFN-γ) develop cardiac pathology [6,7]. Remarkably, heart-specific autoimmune inflammation has been shown to be a consequence of impaired central tolerance induction to α-MyHC during T-cell development in mice and in humans [8]. CD4 + T-cell-orchestrated immune responses are driven by MHC class II (MHCII) mediated antigen presentation. MHCII is primarily expressed on professional APCs. Cardiac APCs were suggested to present cardiac myosin before the onset of cardiac pathology [9], and DCs, the major APC subset able to initiate primary immune responses, were shown to be critical for ...

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Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis

Cited by 142 publications

References 39 publications

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

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

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

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