A P2X7 receptor antagonist attenuates experimental autoimmune myocarditis via suppressed myocardial CD4+ T and macrophage infiltration and NADPH oxidase 2/4 expression in mice

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.

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Immunomodulatory Effects of Erythropoietin on the Experimental Autoimmune Myocarditis of Rats

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2005.08.188 ◽

2005 ◽

Vol 11 (9) ◽

pp. S284

Author(s):

Hisahito Shinagawa ◽

Takayuki Inomata ◽

Hironari Nakano ◽

Toshimi Koitabashi ◽

Tsutomu Ohsaka ◽

...

Keyword(s):

Immunomodulatory Effects ◽

Autoimmune Myocarditis ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

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Anitschkow cells in experimental autoimmune myocarditis.

Circulation ◽

10.1161/01.cir.86.5.1659 ◽

1992 ◽

Vol 86 (5) ◽

pp. 1659-1660 ◽

Cited By ~ 3

Author(s):

J T Beranek

Keyword(s):

Autoimmune Myocarditis ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

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Abstract 129: Suppressor of Cytokine Signaling 1 in Dendritic Cells Inhibits Myocardial Inflammation in Experimental Autoimmune Myocarditis

Circulation Research ◽

10.1161/res.111.suppl_1.a129 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Kazuko Tajiri ◽

Kyoko Imanaka-Yoshida ◽

Michiaki Hiroe ◽

Nobutake Shimojo ◽

Satoshi Sakai ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cytokine Signaling ◽

Autoimmune Myocarditis ◽

Dc Function ◽

Autoreactive T Cell ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

Introduction: Autoimmunity is considered to play an important role in the development of myocarditis and dilated cardiomyopathy. Recent reports have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies. Suppressor of cytokine signaling1 (SOCS1) is an intracellular, cytokine-inducible protein that regulates the responses of immune cells to cytokines. We therefore hypothesized that overexpression of SOCS1 may inhibit the inflammation of myocarditis and cardiomyopathy. Methods and Results: Myocarditis was induced by subcutaneous immunization with cardiac specific peptides derived from α-myosin heavy chain in BALB/c mice on days 0 and 7. Plasmid DNA encoding SOCS1 (pSOCS1) was injected intraperitoneally into mice on days 0, 5 and 10. pSOCS1 treatment significantly decreased heart-to-body weight ratios and the number of infiltrating cells in the heart. Echocardiography showed preserved contractile function in pSOCS1-treated mice. Although autoimmune myocarditis is a CD4+ T cell-mediated disease, pSOCS1 treatment does not have a direct suppressive effect on autoreactive T-cell activation. The introduced pSOCS1 suppressed proinflammatory cytokine production and STAT1 phosphorylation in dendritic cells (DCs). In addition, the proliferative responses of autoreactive CD4+ T cells co-cultured with DCs from pSOCS1-treated mice were much weaker than those of cells cultured with DCs from control plasmid-injected mice. These results suggested that the inoculated pSOCS1 may have been transfected into DCs and impaired DC function in vivo. Conclusion: The administration of pSOCS1 protected mice from the development of experimental autoimmune myocarditis, which was mediated by the inhibition of DC function that in turn reduced the activation of autoreactive CD4+ T cells.

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Abstract 14723: Autoreactive T Lymphocytes Activate Cardiac Endothelium Independently of Tnf-α and Cause Endothelial Dysfunction Through Exosomes in Experimental Autoimmune Myocarditis

Circulation ◽

10.1161/circ.142.suppl_3.14723 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Filip Rolski ◽

Marcin Czepiel ◽

Kazimierz Weglarczyk ◽

Maciej Siedlar ◽

Gabriela Kania ◽

...

Keyword(s):

T Cells ◽

Endothelial Dysfunction ◽

T Lymphocytes ◽

Conditioned Medium ◽

Autoimmune Myocarditis ◽

Autoreactive T Cells ◽

Tnf Α ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune ◽

Stimulation Of

Background: Inflammatory heart diseases represent an important clinical problem, nonetheless data regarding activation of cardiac microvascular endothelial cells (MVECs) are limited. Aim: To examine influence of TNF-α and exosomes produced by heart-reactive CD4+ T lymphocytes on activation of cardiac MVECs. Methods: Experimental autoimmune myocarditis (EAM) was induced in wild-type (WT) and TNF-α-deficient (TNF-KO) mice. CD4+ T lymphocytes were isolated from EAM mice at day 21 and activated in vitro to produce conditioned medium and exosomes. Activation of MVECs was assessed by specific assays and leukocyte-to-endothelial adhesion was analysed under shear flow condition using the BioFlux microfluidic system. Results: TNF-KO mice showed lower prevalence of myocarditis when compared to WT mice (50% vs. 90%). Stimulation of MVECs with secretome of antigen-activated autoreactive T cells resulted in upregulation of adhesion molecules (ICAM-1, VCAM-1 and P-selectin), increased ROS and decreased NO production. Addition of anti-TNF-α neutralizing antibodies effectively blocked adhesion of leukocytes to MVECs activated with the conditioned medium. Endothelial activation and dysfunction induced by the conditioned medium were independent of TNF-α produced by T cells. Stimulation of MVECs with T cell-derived exosomes increased ROS and decreased levels of NO and eNOS activation, but exosomes neither increased expression of adhesion molecules in MVECs nor induced their ability to bind leukocytes. Conclusions: TNF-α promotes MVEC activation and EAM development. In this model, autoreactive T cells activate MVECs, and TNF-a produced by MVECs rather than T cells is essential in this process. On the other hand, endothelial dysfunction caused by T cells seems to be mediated mainly by exosomes.

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Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248417725058 ◽

2017 ◽

Vol 23 (1) ◽

pp. 89-97 ◽

Cited By ~ 1

Author(s):

Monika Skrzypiec-Spring ◽

Katarzyna Haczkiewicz ◽

Agnieszka Sapa ◽

Tomasz Piasecki ◽

Joanna Kwiatkowska ◽

...

Keyword(s):

Heart Failure ◽

Troponin I ◽

Heart Function ◽

Heart Diseases ◽

Acute Myocarditis ◽

Study Groups ◽

Matrix Metalloproteinase 2 ◽

Autoimmune Myocarditis ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

Aims: Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases’ (MMPs) activation have not been elucidated. Methods and Results: Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. Conclusions: The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation.

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