scholarly journals Bazedoxifene Regulates Th17 Immune Response to Ameliorate Experimental Autoimmune myocarditis via Inhibition of STAT3 Activation

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Wang ◽  
Tianshu Liu ◽  
Xiongwen Chen ◽  
Qiaofeng Jin ◽  
Yihan Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Th17 Cells ◽  
Specific Treatment ◽  
Inflammatory Factors ◽  
Autoimmune Myocarditis ◽  
Cardiac Inflammation ◽  
Inflammatory Heart Disease ◽  
Stat3 Signaling ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Myocarditis is a type of inflammatory cardiomyopathy that has no specific treatment. Accumulating evidence suggests that Th17 cells play a prominent role in the pathogenesis of myocarditis. Interleukin-(IL)-6-mediated signal transducer and activation of transcription 3 (STAT3) signaling is essential for Th17 cell differentiation and secretion of inflammatory cytokines. Bazedoxifene inhibits IL-6/STAT3 signaling in cancer cells, but its effect on the Th17 immune response induced by myocarditis remains unknown. Here we explore the effect of Bazedoxifene on Th17 immune response and cardiac inflammation in a mouse model of experimental autoimmune myocarditis, which has been used to mimic human inflammatory heart disease. After eliciting an immune response, we found Bazedoxifene ameliorated cardiac inflammatory injury and dysfunction. Th17 cells and related inflammatory factors in splenic CD4+ T cells at day 14 and in the heart at day 21 were increased, which were reduced by Bazedoxifene. Furthermore, Bazedoxifene could regulate autophagy induction in polarized Th17 cells. In conclusion, Bazedoxifene affected STAT3 signaling and prevented cardiac inflammation deterioration, so may provide a promising therapeutic strategy for the treatment of experimental autoimmune myocarditis (EAM).

scholarly journals Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor, ameliorates experimental autoimmune myocarditis by suppressing cathepsin-G activity

2020 ◽  
Author(s):  
Yuka Shiheido-Watanabe ◽  
Yasuhiro Maejima ◽  
Shun Nakagama ◽  
Natsuko Tamura ◽  
Takeshi Kasama ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Th17 Cells ◽  
Underlying Mechanism ◽  
Dipeptidyl Peptidase ◽  
Cathepsin G ◽  
Autoimmune Myocarditis ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitor ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background There is a compelling need for establishing effective therapy for autoimmune myocarditis which primarily manifest as chest pain, heart failure or sudden death. Although our group have previously shown that dipeptidyl peptidase-4 (DPP-4) aggravates experimental autoimmune myocarditis (EAM), the detailed underlying mechanism remains to be unelucidated. Methods The effects of linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor, on cardiac function were investigated by treating mouse EAM models and elucidated the role of DPP-4 on EAM using proteomic approaches. Results Immunohistochemical analyses demonstrated that the number of Th17 cells expressing high level of DPP-4 infiltrated to EAM myocardium was significantly attenuated by linagliptin treatment. MS/MS-based analyses demonstrated that DPP-4 binds to cathepsin-G in EAM hearts. DPP-4 also protects cathepsin-G activity by inhibiting the activity of SerpinA3N, a protease inhibitor that catalyzes cathepsin-G. The activity of cathepsin-G and the level of Angiotensin II were markedly elevated in EAM myocardium; this effect was reversed by linagliptin treatment. Furthermore, we found that linagliptin suppresses oxidative stress in EAM hearts. Conclusions DPP-4 physically interacts with cathepsin-G, which, in turn, suppresses SerpinA3N; this promotes angiotensin II accumulation in EAM hearts. Thus, DPP-4 derived from Th17 cells could aggravate cardiac dysfunction during EAM.

scholarly journals Blocking LFA-1 Aggravates Cardiac Inflammation in Experimental Autoimmune Myocarditis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1267 ◽  
Author(s):  
Ludwig T. Weckbach ◽  
Andreas Uhl ◽  
Felicitas Boehm ◽  
Valentina Seitelberger ◽  
Bruno C. Huber ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Ratio ◽  
Heart Weight ◽  
Lymphocyte Function ◽  
Body Weight Ratio ◽  
Antibody Treatment ◽  
Autoimmune Myocarditis ◽  
Cardiac Inflammation ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

The lymphocyte function-associated antigen 1 (LFA-1) is a member of the beta2-integrin family and plays a pivotal role for T cell activation and leukocyte trafficking under inflammatory conditions. Blocking LFA-1 has reduced or aggravated inflammation depending on the inflammation model. To investigate the effect of LFA-1 in myocarditis, mice with experimental autoimmune myocarditis (EAM) were treated with a function blocking anti-LFA-1 antibody from day 1 of disease until day 21, the peak of inflammation. Cardiac inflammation was evaluated by measuring infiltration of leukocytes into the inflamed cardiac tissue using histology and flow cytometry and was assessed by analysis of the heart weight/body weight ratio. LFA-1 antibody treatment severely enhanced leukocyte infiltration, in particular infiltration of CD11b+ monocytes, F4/80+ macrophages, CD4+ T cells, Ly6G+ neutrophils, and CD133+ progenitor cells at peak of inflammation which was accompanied by an increased heart weight/body weight ratio. Thus, blocking LFA-1 starting at the time of immunization severely aggravated acute cardiac inflammation in the EAM model.

scholarly journals The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

2017 ◽  
Vol 42 (2) ◽  
pp. 713-728 ◽  
Author(s):  
Bangwei Wu ◽  
Huanchun Ni ◽  
Jian Li ◽  
Xinyu Zhuang ◽  
Jinjin Zhang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Troponin I ◽  
Tissue Injury ◽  
H9c2 Cells ◽  
Autoimmune Myocarditis ◽  
Cardiac Inflammation ◽  
Experimental Autoimmune Myocarditis ◽  
Tlr4 Activation ◽  
The Impact ◽  
Experimental Autoimmune

Background/Aims: Mitochondrial DNA (mtDNA), acting as a newly found ‘danger-associated molecular patterns’ (DAMPs), is released into circulation upon tissue injury and performs as a considerable activator of inflammation and immune response. However, the role of circulating mtDNA in experimental autoimmune myocarditis (EAM) as well as Toll like receptor4 (TLR4) mediated cardiac inflammation and injury remains unknown. Methods: A model of EAM was established in BALB/c mice by immunization with porcine cardiac myosin. Lipopolysaccharide (LPS) was used to stimulate TLR4 activation in EAM mice and H9C2 cells. Results: LPS stimulation significantly aggravated cardiac inflammation and tissue injury in EAM, as demonstrated by increased myocardium inflammatory cell infiltration, and up-regulated inflammatory cytokines and troponin I(TnI) level in serum. Circulating mtDNA level was increased in EAM and TLR4 activation led to a greater elevation, which may be related to Reactive oxygen species (ROS) stress involved mtDNA damage characterized by reduced mtDNA copy number in myocardium tissue. In addition, the expression of Toll like receptor9 (TLR9), a ligand of mtDNA, was significantly up-regulated in the myocardium of EAM and EAM LPS group; meanwhile, TLR9 inhibition by ODN 2088 caused an inhibited apoptosis in LPS treated H9C2 cells. Moreover, in EAM and EAM LPS group, simultaneously giving ODN 2088 treatment significantly ameliorated cardiac inflammation and tissue injury compared with untreated group. Conclusion: Increased circulating mtDNA combined with upregulated TLR9 expression may corporately play a role in EAM as well as TLR4 activation mediated cardiac inflammation and injury.

scholarly journals Sacubitril/Valsartan Alleviates Experimental Autoimmune Myocarditis by Inhibiting Th17 Cell Differentiation Independently of the NLRP3 Inflammasome Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Liang ◽  
Bai-Kang Xie ◽  
Pei-Wu Ding ◽  
Min Wang ◽  
Jing Yuan ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nlrp3 Inflammasome ◽  
Th17 Cell ◽  
Troponin T ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Autoimmune Myocarditis ◽  
Th17 Cell Differentiation ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Sacubitril/valsartan (Sac/Val) is a recently approved drug that is commonly used for treatment of heart failure. Several studies indicated that Sac/Val also regulated the secretion of inflammatory factors. However, the effect and mechanism of this drug modulation of inflammatory immune responses are uncertain. In this study, an experimental autoimmune myocarditis (EAM) mouse model was established by injection of α-myosin-heavy chain peptides. The effect of oral Sac/Val on EAM was evaluated by histological staining of heart tissues, measurements of cardiac troponin T and inflammatory markers (IL-6 and hsCRP). The effects of Sac/Val on NLRP3 inflammasome activation and Th1/Th17 cell differentiation were also determined. To further explore the signaling pathways, the expressions of cardiac soluble guanylyl cyclase (sGC) and NF-κB p65 were investigated. The results showed that Sac/Val downregulated the inflammatory response and attenuated the severity of EAM, but did not influence NLRP3 inflammasomes activation. Moreover, Sac/Val treatment inhibited cardiac Th17 cell differentiation, and this might be associated with sGC/NF-κB p65 signaling pathway. These findings indicate the potential use of Sac/Val for treatment of myocarditis.

Abstract 403: Critical Role for Dipeptidyl Peptidase-4 Activity in the Pathogenesis of Experimental Autoimmune Myocarditis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yusuke Ito ◽  
Natsuko Tamura ◽  
Mitsuaki Isobe
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Th17 Cells ◽  
Dipeptidyl Peptidase ◽  
Left Ventricular Ejection ◽  
Autoimmune Myocarditis ◽  
Dipeptidyl Peptidase 4 ◽  
Cont Group ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Autoimmune myocarditis is the most common cause of heart failure among young adults and is a major precursor of dilated cardiomyopathy. We have shown that dipeptidyl peptidase-4 (DPP-4) plays a detrimental role in the pathogenesis of experimental autoimmune myocarditis (EAM) in mice. To elucidate how DPP-4 induces cardiac dysfunction in the EAM heart, mouse EAM models were given normal diet (CONT-group, N = 6), or a diet mixed with linagliptin, a potent DPP-4 inhibitor (83 mg/kg chow corresponding to around 3 mg/kg oral dosing) (LINA-group, N = 6). After 21-day of EAM induction, left ventricular ejection fraction was significantly higher in LINA-group than in CONT-group (72.6 ± 6.6%* vs. 60.1 ± 9.2%, * P < 0.05). Immunostaining demonstrated that the number of RORγt-positive Th17 cells, a subset of T-lymphocytes expressing high level of enzymatically active DPP-4, infiltrated to the EAM hearts was significantly smaller in LINA-group than in CONT-group (46.9 ± 2.4 RFU* vs. 116.8 ± 8.6 RFU, * P < 0.05). Consistently, the activity of DPP-4 in the EAM hearts was significantly lower in LINA-group than in CONT-group. Mass spectrometry analysis using lysates from the EAM hearts co-immunoprecipitated with Flag-DPP-4 recombinant protein demonstrated that DPP-4 interacts with cathepsin-G (CTSG), a plasma membrane-bound serine protease, in the EAM hearts. Co-immunoprecipitation assay verified the physical interaction between CTSG and DPP-4. The CTSG activity in the EAM hearts was markedly elevated, and treatment with linagliptin effectively suppressed the CTSG activity in the EAM hearts. We also found that DPP-4 significantly suppressed the activity of α1-antichymotrypsin, a protease which can catalyzes CTSG and is activated in response to EAM. Finally, we demonstrated that the level of angiotensin II, a major product catalyzed by CTSG, in the EAM hearts was significantly decreased in LINA-group than in CONT-group. Thus, these results suggest that DPP-4 expressing on the surface of Th17 cells physically interacts with CTSG, thereby enhancing CTSG activity by suppressing α1-antichymotrypsin, which, in turn, promoting the accumulation of angiotensin II, in the EAM hearts. In conclusion, DPP-4 derived from Th17 cells aggravates cardiac dysfunction during EAM.

scholarly journals Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Luisa Barcena ◽  
Sarah Jeuthe ◽  
Maximilian H. Niehues ◽  
Sofya Pozdniakova ◽  
Natalie Haritonow ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Female Rats ◽  
Male Rats ◽  
Inflammatory Factors ◽  
Autoimmune Myocarditis ◽  
Male And Female Rats ◽  
Inflammatory Phenotype ◽  
Experimental Autoimmune Myocarditis ◽  
Anti Inflammatory ◽  
Experimental Autoimmune

Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.

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