scholarly journals RIP1/RIP3/MLKL Mediates Myocardial Function Through Necroptosis in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yujing Wu ◽  
Zhenzhong Zheng ◽  
Xiantong Cao ◽  
Qing Yang ◽  
Vikram Norton ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Function ◽  
Viral Myocarditis ◽  
Cardiac Myosin ◽  
Autoimmune Myocarditis ◽  
Potential Therapeutic Target ◽  
Inflammatory Infiltration ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds through apoptosis but has no significant effect on autophagy. In contrast, autophagy inhibitor 3-Methyl Adenine (3-MA) increases necroptosis, implying that blockage of autophagy must be compensated through necroptosis. Caspase 8 inhibitor zVAD-fmk blocks apoptosis but increases both necroptosis and autophagy. However, all necroptosis, apoptosis, and autophagy inhibitors independently reduce inflammatory infiltration in cardiomyocytes and improve cardiac conditions. Since apoptosis or autophagy is involved in many important cellular aspects, instead of suppressing these two major cell death processes, Nec1 can be developed as a potential therapeutic target for inflammatory myocarditis.

scholarly journals IL-17 Upregulates MCP-1 Expression via Act1 / TRAF6 / TAK1 in Experimental Autoimmune Myocarditis

2021 ◽  
Author(s):  
xiao huang ◽  
Zhuolun Li ◽  
Xinhe Shen ◽  
na nie ◽  
yan shen
Keyword(s):  
Myocardial Tissue ◽  
Inflammatory Factor ◽  
Mononuclear Cell Infiltration ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Mrna And Protein Expression ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune ◽  
Important Cytokine

Abstract Myocarditis is a myocardial inflammatory infiltration heterogeneous disease. At present, various interventions are not effective in the treatment of myocarditis. IL-17, an important pro‐inflammatory factor secreted mainly by Th17 cells, can promote the expression of multiple cytokines. MCP-1 is an important cytokine that mediates mononuclear cell infiltration. Studies have found that IL-17 could stimulate the expression of MCP-1 to mediate inflammatory infiltration. But the mechanism by which IL-17 induces MCP-1 expression in experimental autoimmune myocarditis (EAM) remains unclear. The purpose of this study is to establish an EAM model to explore the role of Act1/TRAF6/TAK1 cascade in the induction of MCP-1 by IL-17. In the present study, we found that in EAM, IL-17 could stimulate the expression of MCP-1 by activating Act1/TRAF6/TAK1 cascade. After interfering TAK1 with si-TAK1, myocardial tissue inflammation was greatly alleviated, and both MCP-1 mRNA and protein expression were downregulated. In conclusion, IL-17 can activate AP-1, NF-κB via Act1/TRAF6/TAK1 upregulation of MCP-1 expression in EAM.

scholarly journals Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice

2021 ◽  
Vol 22 (3) ◽  
pp. 1426
Author(s):  
Siqi Li ◽  
Kazuko Tajiri ◽  
Nobuyuki Murakoshi ◽  
DongZhu Xu ◽  
Saori Yonebayashi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Programmed Death ◽  
Experimental Autoimmune Myocarditis ◽  
Deficient Mice ◽  
Experimental Autoimmune

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.

scholarly journals Effects of 1, 25-Dihydroxyvitamin D3 on Experimental Autoimmune Myocarditis in Mice

2016 ◽  
Vol 38 (6) ◽  
pp. 2219-2229 ◽  
Author(s):  
Fen Hu ◽  
Lianhua Yan ◽  
Shuai Lu ◽  
Wenhan Ma ◽  
Ya Wang ◽  
...  
Keyword(s):  
Beclin 1 ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Western Blots ◽  
Dihydroxyvitamin D3 ◽  
Multiple Systems ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Background/Aims: Myocarditis is an important inflammatory disease of the heart which causes life-threatening conditions. 1, 25(OH)2 D3 has effects on multiple systems and diseases. The present study was aimed to investigate the effect of 1, 25(OH)2 D3 on experimental autoimmune myocarditis (EAM), and explored the underlying mechanisms involved. Methods: EAM was induced by immunizing BALB/c mice with cardiac α-myosin heavy chain peptides (MyHC-α). 1, 25(OH)2 D3 (1,000 ng/kg once) or vehicle was administered intraperitoneally every other day during the entire experiment. On day 21, transthoracic echocardiography was performed and cardiac inflammatory infiltration was detected by hematoxylin and eosin (HE). The terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) assay, and Western blots for the expression of protein caspase-3 and cleaved-caspase3 were used to evaluate apoptosis. Transmission electron microscopy and Western blots for the expression of protein Beclin-1, LC3B, and P62 were used to evaluate autophagy. Results: The ratio of heart weight/body weight was significantly reduced in 1, 25(OH)2 D3 -treated EAM mice, compared with vehicle -treated ones. 1, 25(OH)2 D3 treatment improved cardiac function, diminished cell infiltration in cardiac, suppressed myocardial apoptosis, decreased the number of autophagosomes, and decreased the protein expression of Beclin-1, LC3-II and p62. Conclusions: The present results demonstrated that administration of 1, 25(OH)2 D3 decreased EAM severity. 1, 25(OH)2 D3 treatment may be a feasible therapeutic approach for EAM.

scholarly journals ROLE OF GREEN-FLUORESCENT-PROTEIN-EXPRESSING T CELLS IN EXPERIMENTAL AUTOIMMUNE MYOCARDITIS

2011 ◽  
Vol 57 (14) ◽  
pp. E228
Author(s):  
Tomoyoshi Yanagisawa ◽  
Takayuki Inomata ◽  
Ichiro Watanabe ◽  
Emi Maekawa ◽  
Tomohiro Mizutani ◽  
...  
Keyword(s):  
T Cells ◽  
Green Fluorescent Protein ◽  
Fluorescent Protein ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Green Fluorescent ◽  
Experimental Autoimmune

TNF-alpha protects from exacerbated autoinflammatory response in mouse model of experimental autoimmune myocarditis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Rolski ◽  
K Weglarczyk ◽  
P Pelczar ◽  
M Siedlar ◽  
B Ludewig ◽  
...  
Keyword(s):  
T Cells ◽  
High Dose ◽  
Wild Type ◽  
Autoimmune Myocarditis ◽  
Heart Failure Patients ◽  
Tnf Α ◽  
Intercellular Adhesion Molecules ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background Myocarditis is an inflammatory heart disease and heart-specific autoimmunity plays an important role in development and progression of the disease. TNF-α is a potent pro-inflammatory cytokine implicated in pathogenesis in many inflammatory diseases. Unexpectedly, clinical studies showed that high dose anti-TNF-α therapy increased hospitalization and mortality of heart failure patients. Purpose To elucidate the role of TNF-α in heart-specific autoimmunity and in activation of cardiac microvascular endothelial cells in autoimmune response. Methods Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice by immunization with α-myosin heavy chain peptide (α-MyHC) together with complete Freund's adjuvant. Development of myocarditis in the absence of adjuvant was analysed in TCR-M mice, which CD4+ T cells expressed transgenic T cell receptor recognizing α-MyHC. The role of TNF-α was addressed using haploinsufficient Tnf+/−, knockout Tnf−/− and TCR-M x Tnf+/− mice. Effects of antigen-dependent T cell response on cardiac microvascular endothelial cell (cMVEC) activation were assessed by flow cytometry, immunoblotting and leukocyte-endothelium adhesion assay. Inflammatory cells were phenotyped using flow cytometry, cytokine production was measured by ELISA. Results EAM induction resulted in reduced prevalence of myocarditis in Tnf+/− and Tnf−/− comparing wild-type mice at day 21 after disease induction. However, Tnf+/− and Tnf−/− mice that developed myocarditis showed higher severity of the disease than wild-type controls. On the other hand, TCR-M x Tnf+/− mice showed exacerbated myocarditis at age of 2 months and were characterized by increased mortality comparing with TCR-M controls. TCR-M Tnf+/− mice showed increased total number of cardiac infiltrates compared to TCR-M controls, but no difference in myeloid subsets were observed. In contrast, Tnf+/− and Tnf−/− mice showed significantly increased percentage of T effector cells in spleens and blood in both myocarditis models. Stimulation with rTNF-α induced expression of intercellular adhesion molecules (ICAM1, VCAM1 and P-selectin) on cMVECs, which was associated with increased ability to bind leukocytes under shear flow conditions. TNF-α deficiency had, however, no impact on antigen-specific activation and proliferation of T-cells. Medium conditioned of antigen-activated wild-type, Tnf+/− and Tnf−/− CD4+ T cells showed similar cMVEC activation measured by increased expression of intercellular adhesion molecules and binding of leukocytes under shear flow condition. Furthermore, Tnf+/− and Tnf−/m- myeloid cells showed increased production of IL-6. Conclusions Our data suggest that TNF-α protects the heart from excessive autoimmune reaction by suppressing expansion of autoreactive effector T cells. Thus, this study uncovers a cardioprotective role of proinflammatory TNF-α and potentially can explain the deleterious effect of high dose anti-TNF-α therapy in heart failure patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science Centre Poland

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