scholarly journals A Case of Autoimmune Myocarditis Treated with IL-17 Inhibition

2021 ◽  
Vol 14 ◽  
pp. 201-202
Author(s):  
Atieh Jibbe ◽  
Brett ◽  
Anand Rajpara ◽  
Jacob Whitsitt ◽  
Mark Hamblin
Keyword(s):  
Autoimmune Disease ◽  
Mouse Models ◽  
Heart Muscle ◽  
Systemic Autoimmune Disease ◽  
Future Research ◽  
Autoimmune Myocarditis ◽  
Inflammation Targeting ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Myocarditis is defined as inflammation targeting the heart muscle. Autoimmune myocarditis is a subtype of myocarditis that can occur as an isolated entity in which the primary targeted organ is the heart or as part of a systemic autoimmune disease. The pathogenesis of autoimmune myocarditis has been studied using experimental autoimmune myocarditis mouse models. These studies have established the role of TH17 and IL-17 in the development and progression of myocarditis. While IL-17 inhibition has been tested in these mouse models, there are no reported cases of IL-17 inhibitors being utilized in humans to treat autoimmune myocarditis. We report a patient diagnosed with autoimmune myocarditis in the setting of psoriasis treated initially with prednisone and methotrexate without improvement. The patient was then started on an IL-17 inhibitor secukinumab, directly targeting the immune mechanisms found to be responsible for autoimmune myocarditis and its progression as evidenced by the experimental autoimmune myocarditis mouse models. We provide nuclear scan imaging pre- and post-treatment with secukinumab documenting resolution of our patient’s autoimmune myocarditis. This novel case highlighting the success of IL17 inhibition in treating autoimmune myocarditis, a disease with no truly effective treatment and with potentially devastating consequences, provides an exciting avenue for future research in larger patient populations to further assess the efficacy of this treatment modality.

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

scholarly journals STAT4 silencing underlies a novel inhibitory role of microRNA-141-3p in inflammation response of mice with experimental autoimmune myocarditis

2019 ◽  
Vol 317 (3) ◽  
pp. H531-H540 ◽  
Author(s):  
Aiqun Pan ◽  
Yuying Tan ◽  
Zhihao Wang ◽  
Guoliang Xu
Keyword(s):  
Body Weight ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Heart Weight ◽  
Inflammatory Factor ◽  
Body Weight Ratio ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

As an inflammatory disease afflicting the heart muscle, autoimmune myocarditis (AM) represents one of the foremost causes of heart failure. Accumulating evidence has implicated microRNAs (miRNAs) in the process of inflammation and autoimmunity. Hence, the current study aimed to investigate the mechanism by which miR-141-3p influences experimental AM (EAM). An EAM mouse model was established using 6-wk old male BALB/c mice, after which the expression of miR-141-3p and STAT4 was measured. Gain-of-function and loss-of-function investigations were performed to identify the functional role of miR-141-3p and STAT4 in EAM. Heart weight-to-body weight ratio, cardiac function, and degree of inflammation, as well as the levels of inflammation factors (IFN-γ, TNF-α, IL-2, IL-6, and IL-17) in the serum were detected. STAT4 was subsequently verified to be upregulated, and miR-141-3p was downregulated in the EAM mice. Furthermore, the overexpression of miR-141-3p or silencing of STAT4 was observed to reduce the heart weight-to-body weight ratio of EAM mice and improve cardiac function, while alleviating the degree of inflammatory cell infiltration in the myocardial tissue. Meanwhile, the overexpression of miR-141-3p was identified to diminish serum inflammatory factor levels by downregulating STAT4. Additionally, miR-141-3p could bind to STAT4 to downregulate its expression, ultimately mitigating inflammation and inducing an anti-inflammatory effect in EAM mice. Taken together, upregulation of miR-141-3p alleviates the inflammatory response in EAM mice by inhibiting STAT4, providing a promising intervention target for the molecular treatment of AM. NEW & NOTEWORTHY miR-141-3p is poorly expressed, and STAT4 is upregulated in experimental autoimmune myocarditis (EAM) mice. Overexpressing miR-141-3p inhibits EAM. miR-141-3p binds to and suppresses STAT4 expression. miR-141-3p overexpression inhibits inflammatory factors by downregulating STAT4. This study provides new insights into the treatment of autoimmune myocarditis.

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.

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