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Coxsackievirus B3 (CVB3) is an important cause of viral myocarditis with no vaccine available in clinic. Herein we constructed an exosome-based anti-CVB3 vaccine (Exo-VP1), and compared its immunogenicity and immunoprotection with our previously reported recombinant VP1 protein (rVP1) vaccine. We found that compared with the 25 μg rVP1 vaccine, Exo-VP1 vaccine containing only 2 μg VP1 protein induced much stronger CVB3-specific T cell proliferation and CTL responses (with an increase of more than 70% and 40% respectively), and elicited greater splenic Th1/CTL associated cytokines (IFN-γ, TNF-α and IL-12). Furthermore, higher IgG levels with increased neutralizing titers and avidity were also evidenced in Exo-VP1 group. Consistently, Exo-VP1 group exhibited enhanced resistance to viral myocarditis than rVP1 vaccine, reflected by reduced cardiac viral loads, improved myocardial inflammation and an increased survival rate. Collectively, we reported that Exo-VP1 might present a more potent CVB3 vaccine candidate than rVP1 vaccine. • Exo-VP1 had good size stability • It evoked higher CTL and IgG levels than rVP1. • It enhanced mice resistant to myocarditis. [ABSTRACT FROM AUTHOR]

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis. To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis. Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings. Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis. [ABSTRACT FROM AUTHOR]

• Myocarditis, a long-term complication of coronavirus disease 2019 (COVID-19) is an inflammatory condition involving the myocardium of the heart. The interplay among long COVID, immune cells, and autoimmunity in the pathogenesis of myocarditis is still not clear. However, the pathogenesis of long COVID myocarditis involving ACE2 receptor and COVID-19 spike protein is widely accepted. • A comprehensive understanding of the biomarkers involved is necessary for the development of pathogenesis-based therapies and the repurposing of the already available therapies. Various biomarkers including troponin, lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, galectin-3 (GAL-3), growth differentiation factor 15 (GDF-15), presepsin, soluble suppression of tumorigenicity (sST2), copeptin, and interleukins, are helpful in the diagnosis and prognosis of long COVID myocarditis. • Invasive techniques like endomyocardial biopsy (EMB) and non-invasive techniques like transthoracic echocardiography (TTE), cardiac magnetic resonance imaging (MRI) are also beneficial in the management. • The current available treatments include glucocorticoids, intravenous immunoglobins (IVIG), interleukin antagonists, rituximab, colchicine, and aldose reductase inhibitor AT001, along with inotropes and oxygen support. Despite these therapies, reports of mortality in several studies despite treatment with these drugs, imply the importance of discovering new treatment strategies. Hence, it is recommended that further research must be carried out in patients with myocarditis. Infectious diseases are a cause of major concern in this twenty-first century. There have been reports of various outbreaks like severe acute respiratory syndrome (SARS) in 2003, swine flu in 2009, Zika virus disease in 2015, and Middle East Respiratory Syndrome (MERS) in 2012, since the start of this millennium. In addition to these outbreaks, the latest infectious disease to result in an outbreak is the SARS-CoV-2 infection. A viral infection recognized as a respiratory illness at the time of emergence, SARS-CoV-2 has wreaked havoc worldwide because of its long-lasting implications like heart failure, sepsis, organ failure, etc., and its significant impact on the global economy. Besides the acute illness, it also leads to symptoms months later which is called long COVID or post-COVID-19 condition. Due to its ever-increasing prevalence, it has been a significant challenge to treat the affected individuals and manage the complications as well. Myocarditis, a long-term complication of coronavirus disease 2019 (COVID-19) is an inflammatory condition involving the myocardium of the heart, which could even be fatal in the long term in cases of progression to ventricular dysfunction and heart failure. Thus, it is imperative to diagnose early and treat this condition in the affected individuals. At present, there are numerous studies which are in progress, investigating patients with COVID-19-related myocarditis and the treatment strategies. This review focuses primarily on myocarditis, a life-threatening complication of COVID-19 illness, and endeavors to elucidate the pathogenesis, biomarkers, and management of long COVID myocarditis along with pipeline drugs in detail. [ABSTRACT FROM AUTHOR]

Pathological innate and adaptive immune response upon viral infection may lead to cardiac injury and dysfunction. Stabilin-1 is a scavenger receptor that regulates several aspects of the innate immunity. Whether stabilin-1 affects the inflammatory response during viral myocarditis (VM) is entirely unknown. Here, we assess the role of stabilin-1 in the pathogenesis of VM and its suitability as a therapeutic target. Genetic loss of stabilin-1 increased mortality and cardiac necrosis in a mouse model of human Coxsackievirus B3 (CVB3)-induced myocarditis. Absence of stabilin-1 significantly reduced monocyte recruitment and strongly reduced the number of alternatively activated anti-inflammatory macrophages in the heart, enhancing a pro-inflammatory cardiac niche with a detrimental T lymphocyte response during VM. Yeast two-hybrid screening, confirmed by affinity chromatography, identified fibronectin as a stabilin-1 interacting partner. Absence of stabilin-1 specifically decreased monocyte adhesion on extracellular fibronectin in vitro. Loss of Type III repeats Extra Domain A (EDA) of fibronectin during VM also increased the mortality and cardiac necrosis as in stabilin-1 knockout mice, with reduced monocytic cardiac recruitment and increased T lymphocyte response. Collectively, stabilin-1 has an immune-suppressive role of limiting myocardial damage during VM, regulating anti-inflammatory monocyte-recruitment to the site of inflammation. [Display omitted] • Stabilin-1 is expressed in myeloid cells in mouse and human viral myocarditis. • Loss of stabilin-1 increased mortality and cardiac necrosis in murine viral myocarditis. • Stabilin-1 is required for anti-inflammatory macrophage phenotype differentiation. • Stabilin-1 influences monocyte recruitment through binding with extracellular fibronectin. [ABSTRACT FROM AUTHOR]

The condition of COVID-19-related myocarditis has emerged as a prominent contributor to COVID-19 mortality. As the epidemic persists, its incidence continues to rise. Despite ongoing efforts, the elucidation of COVID-19-related myocarditis underlying molecular mechanisms still requires further investigation. Hub genes for COVID-19-related myocarditis were screened by integrating gene expression profile analysis via differential expression in COVID-19 (GSE196822) and myocarditis (GSE148153 and GSE147517). After verification with independent datasets (GSE211979, GSE167028, GSE178491 and GSE215865), the hub genes were studied using a range of systems-biology approaches, such as ceRNA, TF-mRNA networks and PPI networks, as well as gene ontology, pathway enrichment, immune infiltration analysis and drug target identification. TBKBP1 and ERGIC1 were identified as COVID-19-related myocarditis hub genes via integrated bioinformatics analysis. In addition, receiver operating characteristic curves constructed based on the expression levels of TBKBP1 and ERGIC1 could effectively distinguish healthy control individuals from patients with COVID-19. Functional enrichment analysis suggested several enriched biological pathways related to inflammation and immune response. Immune cell changes correlated with TBKBP1 and ERGIC1 levels in patients with COVID-19 or patients with COVID-19 and myocarditis. Tamibarotene, methotrexate and theophylline were identified as a potential drug targeting TBKBP1 and ERGIC1. TBKBP1 and ERGIC1 were identified as crucial genes in the development of COVID-19-related myocarditis and have demonstrated a strong association with innate antiviral immunity. The present work may be helpful for further investigation of the molecular mechanisms and new therapeutic drug targets correlated with myocarditis in COVID-19. • Potential drugs targeting the central genes of novel coronavirus-associated myocarditis were predicted. This study will provide new molecular mechanisms and targets for novel coronavirus pneumonia-associated myocarditis. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have changed the landscape of cancer therapy, but their use carries a high risk of cardiac immune related adverse events (iRAEs). With the expanding utilization of ICI therapy, there is a growing need to understand the underlying mechanisms behind their anti-tumor activity as well as their immune-mediated toxicities. In this review, we will focus on clinical characteristics and immune pathways of ICI cardiotoxicity, with an emphasis on single-cell technologies used to gain insights in this field. We will focus on three key areas of ICI-mediated immune pathways, including the anti-tumor immune response, the augmentation of the immune response by ICIs, and the pathologic "autoimmune" response in some individuals leading to immune-mediated toxicity, as well as local factors in the myocardial immune environment predisposing to autoimmunity. Discerning the underlying mechanisms of these immune pathways is necessary to inform the development of targeted therapies for ICI cardiotoxicities and reduce treatment related morbidity and mortality. [Display omitted] • Immune checkpoint inhibitors (ICI) carry a risk for a variety of cardiac immune related adverse events (iRAEs). • Single-cell technologies allow understanding of ICI tumor toxicity immune pathways, as well as off-target effects in the heart. • Both human and mice data are necessary to discover targets for ICI cardiotoxicity therapy development and reduce morbidity/mortality. [ABSTRACT FROM AUTHOR]

To assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). Peripheral blood samples were collected from 9 patients diagnosed with AVMC and 9 healthy controls (HC) in the Affiliated Hospital of Qingdao University from July 2021 to September 2022. The exosomal miRNA expression were tested using RNA high-throughput sequencing. We conducted the GO and KEGG functional analysis to predict the potential molecular, biological functions and related signaling pathways of miRNAs in exosomes. Target genes of exosomal miRNAs were predicted and miRNA-target gene network was mapped using gene databases. Differentially expressed exosomal miRNAs were selected and their expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) to verify the sequencing results. P < 0.05 and Fold Change>2 were considered as cut-off value to screen miRNAs that were differently expressed. This study identified 14 upregulated and 14 downregulated exosome-derived miRNAs. GO and KEGG analysis showed that differentially expressed miRNAs may be related to β-catenin binding, DNA transcription activities, ubiquitin ligase, PI3K-Akt, FoxO, P53, MAPK, and etc.. The target genes of differentially expressed miRNAs were predicted using gene databases. Real-time PCR confirmed the upregulation of hsa-miR-548a-3p and downregulation of hsa-miR-500b-5p in AVMC. Hsa-miR-548a-3p and hsa-miR-500b-5p could serve as a promising biomarker of AVMC. Exosomal miRNAs may have substantial roles in the mechanisms of AVMC. • Hsa-miR-548a-3p and hsa-miR-500b-5p could serve as promising biomarkers of AVMC. • Exosomal miRNAs may have substantial roles in the mechanisms of AVMC. • Target genes of exosomal miRNAs may be related to the pathogenesis of myocarditis. [ABSTRACT FROM AUTHOR]

Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI. • The first study to demonstrate that cardiac reprogramming suppresses inflammation. • Cardiac reprogramming reduces inflammatory gene expression in CFs after MI. • Cardiac reprogramming suppresses the inflammatory profile of macrophages in chronic MI. • Cardiac reprogramming reduced CCR2+ inflammatory macrophages in remote areas. • Cardiac reprogramming may be a novel strategy for chronic MI and HF treatment. [ABSTRACT FROM AUTHOR]

Terbuthylazine (TBA), a triazine herbicide, is extensively employed in agriculture for its wide range of effectiveness. However, prolonged utilization of TBA can pose a potential hazard to animals and human health. Here, a total of 180 broiler chickens (Gallus gallus) were stochastically assigned to three groups (control group, 0.4 mg/kg TBA group, and 4 mg/kg TBA group) for investigating the impact of TBA on cardiotoxicity. The results revealed that TBA exposure resulted in pathological alterations in the myocardium. Moreover, TBA exposure activated cGAS-STING pathway and markedly elevated the mRNA and protein expression levels of innate immune response (cGAS, STING, TBK1, and IRF3) in myocardium. Additionally, NF-κB signal was also activated under TBA exposure, which was characterized by the increasing mRNA expression levels of NF-κB, IKKα and the protein expression levels of p-NF-κB/NF-κB, IKKα, p-IκBα/IκBα in the TBA treatment groups. Meanwhile, the expression of pro-inflammatory cytokines (TNF-α and IL-1β) were also significantly increased. In summary, our findings suggested that cGAS-STING/NF-κB pathway functionated in the innate immune response and inflammation in myocardium brought on by TBA exposure, which provided new insights into the TBA toxicology. [Display omitted] • TBA induced pathological damage in chicken myocardium. • The innate immune response and inflammation were activated by TBA. • cGAS-STING and NF-κB pathway mediated innate immune response under TBA exposure. [ABSTRACT FROM AUTHOR]

The relative overexpression of Coxsackie and adenoviral receptor (CAR) predisposes children to viral myocarditis. As the foot and mouth disease virus (FMDV) causes fatal myocarditis in calves, lambs, and piglets and belongs to the same family as the Coxsackie virus, we investigated the role of CAR in FMDV induced myocarditis in the suckling mice model. Swiss albino suckling mice of 5 days (n = 24) were divided into two equal groups. One group was inoculated with suckling mice adapted FMDV serotype O at 10 LD 50 , while the other group served as uninfected control. In addition, adult mice (n = 12) served as the control for age related CAR expression and lack of pathogenicity to FMDV. The establishment of myocarditis was confirmed by histopathological changes typical of myocarditis along with immunolocalization of FMDV antigens in the heart of suckling mice. The FMDV inoculated suckling mice group showed a significant upregulation of CAR transcripts by 2.5 folds, overexpression of CAR protein by densitometric analysis of immunoblots, and intense immunolocalization of CAR in the sarcolemma and intercalated discs of cardiomyocytes as compared to the uninfected suckling mice group and adult mice. It was concluded that FMDV infection induced overexpression of CAR in the myocardium of suckling mice. • Foot and mouth disease virus causes myocarditis in 5-day-old suckling mice. • Upregulation of CAR mRNA was 2.5 folds higher in FMDV infected suckling mice as compared to uninfected suckling mice. • FMDV infection induced overexpression of CAR protein in the cardiomyocytes. [ABSTRACT FROM AUTHOR]

Since toll-like receptor 9 (TLR9) or interferon regulatory factor 5 (IRF5) was reported to be associated with the development of myocarditis, we wondered if the TLR9-IRF5 pathway could contribute to the development of coxsackievirus B3 (CVB3)-induced myocarditis. We detected signaling molecules of TLR9-IRF5 pathway in CVB3-infected patients and mice. The results showed that TLR9, IRF5 and its downstream molecules such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly increased, and the increase was correlated with the severity of heart injury during CVB3 infection. In addition, we demonstrated that an AAAG ODN with IRF5 interfering activities significantly decreased the levels of the TLR9-IRF5 pathway molecules in hearts, spleens as well as white blood cells, and alleviated the myocarditis in CVB3-infected mice. The data suggest that interfering TLR9-IRF5 pathway could be an approach to treat CVB3-induced myocarditis. • The TLR9-IRF5 signaling is activated in development of CVB3-inducecd myocarditis. • TLR9-IRF5 signaling aggravates CVB3-induced cardiac damage in mice. • Interfering TLR9-IRF5 signaling could alleviate myocarditis in CVB3-infected mice. • Targeting TLR9-IRF5 signaling pathway could be an approach for treating VMC. [ABSTRACT FROM AUTHOR]

Despite the multiple benefits of vaccination, cardiac adverse Events Following COVID-19 Immunization (c-AEFI) have been reported. These events as well as the severe cardiac involvement reported in Multisystem inflammatory syndrome in children (MIS-C) appear more frequent in young adult males. Herein, we firstly report on the inflammatory profiles of patients experiencing c-AEFI in comparison with age, pubertal age and gender matched MIS-C with cardiac involvement. Proteins related to systemic inflammation were found higher in MIS-C compared to c-AEFI, whereas a higher level in proteins related to myocardial injury was found in c-AEFI. In addition, higher levels of DHEAS, DHEA, and cortisone were found in c-AEFI which persisted at follow-up. No anti-heart muscle and anti-endothelial cell antibodies have been detected. Overall current comparative data showed a distinct inflammatory and androgens profile in c-AEFI patients which results to be well restricted on heart and to persist months after the acute event. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Adiponectin is a hormone that together with its receptors modulates a number of metabolic processes including gluconeogenesis and lipid catabolism. It belongs to the C1QTNF (complement C1q tumor necrosis factor-related protein) family, which has a variety of members with high amino acid sequence homology and overlapping functions. Concentration of adiponectin in blood is inversely correlated with body fat percentage and cardiac risk factors like blood pressure and CRP (C-reactive protein) level. Studies have identified the existence of a cardiac adiponectin system. However, little is known about the role of this system in the pathogenesis of autoimmune myocarditis. Thus, we have studied the involvement of adiponectin in the development of this autoimmune disorder in a mouse model of experimental autoimmune myocarditis (EAM). Methods Adiponectin knockout (ko) and wild type (wt) mice were immunized with cardiac troponin I (cTnI) to induce an EAM. To determine the severity of myocardial damage, inflammation and fibrosis were scored after HE and Afog staining and high sensitivity troponin T (hsTnT) level was measured. To detect if changes in specific inflammatory cell numbers could be observed between the genotypes, we performed immunohistochemical staining to detect T lymphocytes, B lymphocytes and macrophages. The level of the humoral immune response was determined through the measurement of cTnI-specific serum IgG autoantibodies. Relative mRNA expression of different cytokines, C1QTNF family members and adiponectin receptors in the heart tissue was analyzed with qPCR. Results Animals immunized with cTnI developed autoimmune myocarditis with a significant deterioration of cardiac parameters compared to the corresponding control group. The adiponectin ko group immunized with cTnI showed a tendency towards increased inflammation, fibrosis, heart-to-body-weight ratio, infiltration pattern of T lymphocytes, B lymphocytes and macrophages, hsTnT concentration, humoral immune response and mRNA expression of interleukin 6 in the heart tissue and decreased weight gain compared to the wt group immunized with cTnI. However, the difference to the wt group treated with cTnI was not significant. The analysis of cardiac mRNA expression of adiponectin receptors and four C1QTNF family members, most suitable for fulfilling the functions of adiponectin in adiponectin ko mice, did not show any significant differences between adiponectin ko and wt group at all. Conclusion Our study reveals that the absence of adiponectin did not lead to a significantly increased impairment of cardiac function and was also unlikely to be compensated by its receptors or other C1QTNF family members in the murine model of EAM. Here, other synergistic or redundant effects might play a role and must be investigated in further studies to understand the role and function of adiponectin in autoimmune myocarditis. [ABSTRACT FROM AUTHOR]

Inflammation has recently gained tremendous attention as a key contributor in several chronic diseases. While physiological inflammation is essential to counter a wide variety of damaging stimuli and to improve wound healing, dysregulated inflammation such as in the myocardium and vasculature can promote cardiovascular diseases. Given the high severity, prevalence, and economic burden of these diseases, understanding the factors involved in the regulation of physiological inflammation is essential. Like other complex biological phenomena, RNA-based processes are emerging as major regulators of inflammatory responses. Among such processes are cis-regulatory elements in the mRNA of inflammatory genes, noncoding RNAs directing the production or localization of inflammatory cytokines/chemokines, or pathogenic RNA driving inflammatory responses. In this review, we describe several specific RNA-based molecular mechanisms by which physiological inflammation pertaining to cardiovascular diseases is regulated. These include the role of AU-rich element-containing mRNAs, long non-coding RNAs, microRNAs, and viral RNAs. • RNA-based mechanisms control cardiovascular inflammation. • AU-rich element binding proteins regulate pro-inflammatory mRNAs in the heart. • Noncoding RNAs regulate the production and activity of inflammatory proteins. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac hypertrophy related factor (CHRF), a newly recognized long non-coding RNA (lncRNA), is a central regulator in cardiac hypertrophy responses. This study attempted to show the potential role of lncRNA CHRF in bacterial infection caused myocarditis. Methods H9c2 cells were transfected with small interfering RNAs (siRNAs) specific for lncRNA CHRF alone or in combination with miR-221 inhibitor, and then subjected to lipopolysaccharide (LPS). The following parameters were measured: cell viability, apoptosis, reactive oxygen species (ROS) generation, pro-inflammatory cytokines release, microRNA (miR)-221 expression and the activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. Results Silence of lncRNA CHRF impeded the LPS injury to H9c2 cells, as cell viability was increased (p <.05), apoptosis was inhibited (p <.05), ROS generation was decreased (p <.01), and the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α was suppressed (p <.05). However, silence of lncRNA CHRF had no impacts on normal H9c2 cells growth (p >.05). miR-221 was negatively regulated by lncRNA CHRF (p <.01). LncRNA CHRF silence did not protect H9c2 cells against LPS when miR-221 was suppressed (p <.05 or p <.01). Also, the inhibitory effects of lncRNA CHRF silence on the activation of NF-κB and JNK pathways were flattened by miR-221 suppression (p <.05 or p <.01). Conclusion These in vitro data collectively demonstrated that lncRNA CHRF silence protected H9c2 cells against LPS-induced injury via up-regulating miR-221 and modulating NF-κB and JNK pathways. [ABSTRACT FROM AUTHOR]

Abstract Family members of peroxisome proliferator-activated receptors (PPARs), such as PPARγ, have been shown to be effective in regulating T helper 17 (Th17) cell differentiation. However, whether PPARα, another important family member of PPARs, contributes to Th17 cell differentiation remains controversial. In the present study, we show that PPARα may be a negative regulator of Th17 cell differentiation. In CD4+ T cells from PPARα knockout mice, PPARα deficiency enhances IL-17 and IL-6 levels and promotes Th17 cell differentiation. In contrast, in CD4+ T cells from wild type mice, PPARα activation suppresses Th17 cell differentiation. Furthermore, IL-6 neutralizing antibody dose-dependently reduces the activity of STAT3 and down-regulates the protein expression of RORγt in CD4+ T cells from PPARα knockout mice but has no effect on that of wild type mice. On the other hand, in isolated CD4+ T cells from experimental autoimmune myocarditis (EAM) rats, PPARα agonist Fenofibrate decreased the expression of IL-17 and RORγt, increased the expression of Foxp3, while PPARα antagonist MK886 reversed these effects. Importantly, in vivo activation of PPARα ameliorates EAM by suppressing Th17 cell differentiation through reducing the expression of RORγt and phosphorylated STAT3 that are upregulated in EAM hearts. These results imply that PPARα suppresses Th17 cell differentiation through IL-6/STAT3/RORγt signaling pathway and suggest that PPARα may become a molecular target for treating autoimmune myocarditis. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Myocarditis can be caused by several infectious and noninfectious causes. Treatment for myocarditis is still a difficult task in clinical practice. The gut microbiota is related to cardiovascular diseases such as atherosclerosis and hypertension. However, little is known about the role of the gut microbiota in myocarditis. In our study, we tested the hypothesis that gut dysbiosis is associated with myocarditis. We focused on whether fecal microbiota transplantation (FMT) can be used as an effective treatment for myocarditis. We used an experimental autoimmune myocarditis (EAM) mouse model. Fecal samples were isolated from the control and EAM groups for bacterial genome analysis. We observed an increase in microbial richness and diversity in the myocarditis mice. These changes were accompanied by an increased Firmicutes/Bacteroidetes ratio. We also evaluated the efficacy of FMT for the treatment of myocarditis. EAM mouse guts were repopulated with fecal contents from an untreated male mouse donor. We found that myocardial injury was improved by diminished inflammatory infiltration, showing that IFN-γ gene expression in the heart tissue and CD4+IFN-γ+ cells in the spleen were decreased after FMT in EAM mice. We also found that FMT was able to rebalance the gut microbiota by restoring the Bacteroidetes population and reshaping the microbiota composition. Myocarditis is associated with gut microbiota dysbiosis and characterized by an increased F/B ratio. FMT treatment can rebalance the gut microbiota and attenuate myocarditis. Thus, FMT may be a potential therapeutic strategy for the treatment of myocarditis. [ABSTRACT FROM AUTHOR]

Abstract Coxsackievirus B3 (CVB3) is a globally prevalent enterovirus of the Picornaviridae family that is frequently associated with viral myocarditis (VM). Neutrophils, as first responders, may be key cells in determining viral disease outcomes; however, neutrophils have been poorly studied with respect to viral infection. Although neutrophils have been ascribed a relevant role in early cardiac inflammation, their precise role in CVB3 infection has not yet been evaluated. In this study, we aimed to determine if the interaction between human neutrophils and CVB3 could lead to viral replication and/or modulation of neutrophil survival and biological functions, and whether neutrophil depletion in a murine model has a beneficial or harmful effect on CVB3 infection. Our results show that CVB3 interacted with but did not replicate in human neutrophils. Neutrophils recognized CVB3 mainly through endosomal TLR-8, and infection triggered NFκB activation. Virus internalization resulted in increased cell survival, up-regulation of CD11b, enhanced adhesion to fibrinogen and fibronectin, and the secretion of IL-6, IL-1β, TNF-α, and IL-8. Supernatants from infected neutrophils exerted chemotactic activity partly mediated by IL-8. The infected neutrophils released myeloperoxidase and triggered neutrophil extracellular trap formation in the presence of TNF-α. In mice infected with CVB3 , viral RNA was detected in neutrophils as well as in mononuclear cells. After neutrophil depletion, mice showed reduced VM reflected by a reduction in viral titers, cell exudates, and CCL-2 mRNA levels, as well as the abrogation of reactive cardiomyocyte hypertrophy. Our results indicate that neutrophils have relevant direct and indirect roles in the pathogenesis of CVB3-induced VM. Highlights • -Coxsackievirus B3 (CVB3) interacts with, but does not replicate in human neutrophils. • -CVB3 increases neutrophil survival, CD11b expression, cytokine and IL-8 release. • -CVB3 triggers neutrophil release of myeloperoxidase and NETs. • -Neutrophils sense CVB3 mainly through TLR-8 and the activation of NFκB. • -Neutrophil-depleted CVB3-infected mice exhibit reduced viral myocarditis. [ABSTRACT FROM AUTHOR]

Abstract Cardiac fibrosis is an important cardiac remodeling event in the development of inflammation dilated cardiomyopathy （iDCM）. We have previously observed that degradation enhancer of androgen receptor (ASC-J9®) could improve cardiac inflammation and fibrosis. Using Primary CFs, we demonstrated that ASC-J9® attenuates the expression of miR-125b, which subsequently inhibits the generation of collagen. In contrast, overexpressed AR in CFs induced collagen production, increases mir-125b.We also found that inhibition of miR-125b attenuates fibrosis which induced by the overexpression of AR. Our results indentify the functional role for AR as a regulator of cardiac fibrosis due to myocarditis and further show that AR exerts its effect by increasing microRNA-125b expression. Treatment with degradation enhancer of AR limits cardiac fibrosis in iDCM, thereby providing potentially a therapeutic approach for patients with iDCM. Highlights • ASC-J9, a enhancer of AR degradation, attenuation of heart fibrosis in EAM. • Androgen receptor regulates cardiac fibrosis in EAE by increasing microRNA-125b expression. [ABSTRACT FROM AUTHOR]

Abstract Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in numerous kinds of cardiovascular diseases, and their vital role in regulating cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA X-inactive specific transcript (XIST) was upregulated in hypertrophic cardiac of mice and phenylephrine (PE)-treated cardiomyocytes. Next, we observed that inhibition of XIST induced hypertrophic response of cardiomyocyte and overexpression of XIST attenuated cardiomyocyte hypertrophy induced by PE. Furthermore, through online predictive tools and functional experiments, we demonstrated that XIST and S100B were targets of miR-330-3p. XIST and miR-330-3p suppressed each other in a reciprocal way in cardiomyocytes. Additionally, XIST promoted S100B expression through harboring the complementary binding sites with miR-330-3p, eventually prevented cardiac hypertrophy. In conclusion, our findings revealed a novel molecular mechanism that XIST/miR-330-3p/S100B pathway modulates the progression of cardiomyocyte hypertrophy. [ABSTRACT FROM AUTHOR]

Viral myocarditis is a cardiovascular disease that seriously affects human health. Its mechanism is not clear. Coxsackievirus B3 (CVB3) is a member of the picornavirus family and is the leading cause of viral myocarditis. Our group tested the genes in a mouse model of CVB3 virus infection and confirmed that the NADPH oxidase gene had a high expression trend in the acute phase of infection. Whether Nox4, the homologue of NADPH oxidase, participates in the process of viral myocarditis has not been reported. In this study, we found increased expression of Nox4 in viral myocarditis in vivo and in vitro. DPI is a non-specific inhibitor of Nox4 that improved CVB3-induced myocarditis after injection in vivo. DPI also inhibited intracellular ROS release and apoptosis in vitro. Our data indicated that Nox4-dependent ROS production was involved in CVB3-induced myocardial apoptosis. [ABSTRACT FROM AUTHOR]

Recently, we reported the presence of distinct cell clusters named acinar-like cell clusters touching Langerhans islets with thin interstitial surrounding (ATLANTIS) in human pancreas. A morphological study in humans demonstrated that ATLANTIS and islet cell clusters are found together in the microenvironment enclosed by a common basement membrane, and ATLANTIS releases vesicles containing Regenerating gene protein (REG Iα) to islet cell clusters. We examined 1) the presence or absence of ATLANTIS in homozygous Reg I (mouse homologue of human REG Iα) deficient (Reg I −/- ) and wild-type mice, and 2) the possible role of ATLANTIS in the regeneration of beta cell clusters after encephalomyocarditis (EMC) virus (D-variant) infection in Reg I −/- and wild-type mice. ATLANTIS was found in both wild-type and Reg I −/- mice. In both groups, mean blood glucose increased transiently to greater than 14.0 mmol/L at 5 days after EMC virus infection and recovered to baseline at 12 days. At 12 days after EMC virus infection, lower BrdU labeling indices were observed in islet beta cells of Reg I −/- mice compared to wild-type mice. Beta cell volume 12 days after EMC virus infection in Reg I −/- mice did not differ from that of wild-type mice. These results suggest that Reg I, which is released from ATLANTIS to islet beta cell clusters, has a crucial role in beta cell regeneration in EMC virus-induced diabetes. The presence of mechanism(s) other than that mediated by Reg I in beta cell restoration after destruction by EMC virus was also suggested. [ABSTRACT FROM AUTHOR]

Heart disease is the major cause of death and it is broadly recognized that the immune system plays a central role in healthy and injured heart. Here, we focus on the contribution of various subsets of mononuclear phagocytes in the cardiac system. Macrophages and dendritic cells reside in the healthy myocardium to fulfill homeostatic functions and rapidly increase in numbers in diseases like myocardial ischemia and myocarditis to contribute to disease or resolve it. Recent experiments have revealed the extraordinary heterogeneity of cardiac mononuclear phagocytes that differ in origin, lifespan, phenotype and function. Although many studies described cardiac phagocytes in the mouse, subsets of cardiac mononuclear phagocytes can also be broadly found in the human heart, opening up the potential of selective targeting of these cells in a therapeutic setting. Before this goal can be achieved we need better understanding not only of the detrimental but also beneficial functions of these highly diverse cells in the heart. [ABSTRACT FROM AUTHOR]

• AP1 recruits Src1 and PCG1α to transactivate TAC1 in EMCV-induced myocarditis. • In vitro overexpression of the Src1-PCG1α-AP1 members also caused the induction of TAC1 , an increase in SP concentration, initiation of apoptosis, and elevation of proinflammatory cytokine concentrations. • Injection of Src1 inhibitor Gossypol and a PCG1α inhibitor SR1892 in EMCV-infected mice could attenuate myocarditis. Substance P (SP), a neuropeptide consisting of 11 amino acid residues, is involved in the pathogenesis of encephalomyocarditis virus (EMCV)-induced myocarditis by stimulating the production of proinflammatory cytokines. However, the underlying mechanism that regulates SP production is still unknown. In this study, we report the transcriptional regulation of the Tachykinin Precursor 1 (TAC1) gene that encodes SP by a transcriptional complex composed of Steroid Receptor Coactivator 1 (Src1), Peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC1α), and Activator Protein 1 (AP1) transcription factor. Infection of mice with EMCV induced the accumulation of PGC1α and increased TAC1 expression, thereby promoting the secretion of SP, initiating apoptosis, and elevating proinflammatory cytokine levels. In vitro overexpression of the Src1-PGC1α-AP1 members also induced TAC1 expression, increased the SP concentration, initiated apoptosis, and elevated proinflammatory cytokine concentrations. Depletion or inhibition of the Src1-PGC1α-AP1 complex reversed these effects. The administration of gossypol, an Src1 inhibitor, or SR1892, a PGC1α inhibitor, to EMCV-infected mice attenuated myocarditis. Taken together, our results reveal that the upregulation of TAC1 and the secretion of SP in EMCV-induced myocarditis are dependent on the Src1-PGC1α-AP1 complex. Targeting the Src1-PGC1α-AP1 complex may represent a new therapeutic strategy for myocarditis. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that exosome-mediated intercellular microRNAs (miRNA) can influence fulminant myocarditis (FM) pathogenesis between immune and cardiac cells. This study explored plasma exosome miRNA profile in pediatric FM using a small RNA microarray. As per our analysis, we observed the differential expression of 266 miRNAs, including 197 upregulated and 69 downregulated candidate genes. Differentially expressed mRNAs in pediatric FM patients' peripheral blood mononuclear cells (PBMCs) were intersected with miRNA target genes predicting tools to screen for FM-specific target genes. The hub genes and their biological and mechanistic pathways related to inflammation and/or the immune system were identified. CeRNA networks of lncRNAs, circRNAs, miRNAs, and mRNAs between cardiomyocytes and PBMCs were finally established. Furthermore, we verified that hsa-miR-146a-5p, hsa-miR-23a-3p, and hsa-miR-27a-3p had higher expression levels in exosomes of pediatric FM patients by qRT-PCR, and hsa-miR-146a-5p shown high sensitivities and specificities for FM diagnosis. Overall, the results demonstrate that the exosome miRNAs play a regulatory role between immune and cardiac cells and provide research targets. • The first study focusing on altered plasma exosome miRNAs in the pediatric FM cohort. • Focus on intercellular communication between cardiomyocytes and immune cells. • Hsa-miR-23a-3p and hsa-miR-27a-3p are identifed as valuable research targets of FM. • Hsa-miR-146a-5p presents the excellent potential to serve as pediatric FM biomarkers. [ABSTRACT FROM AUTHOR]

Viral myocarditis, which is caused by Coxsackievirus B3 (CVB3) infection, is a leading reason of sudden cardiac death in young adults. Progranulin (PGRN), a pleiotropic growth factor, has been shown to exert anti-inflammatory function in a variety of inflammatory diseases. However, the expression and function of PGRN in the pathogenesis of viral myocarditis remain largely unknown. In this study, we found that PGRN levels in plasma and cardiac tissues were significantly upregulated post CVB3 infection, and negative correlated with disease severity. PGRN deficiency significantly exacerbated, whereas recombinant PGRN treatment attenuated CVB3-induced myocarditis in mice. PGRN downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo , whereas its effect on viral myocarditis was Treg cell independent. Furthermore, PGRN regulated Th1 and Th17 cells differentiation through inhibition of the JAK/STAT pathway. Therefore, our findings reveal a critical role for PGRN in reducing CVB3-induced myocarditis and suggest that PGRN maybe a novel therapeutic treatment for viral myocarditis. [ABSTRACT FROM AUTHOR]

Macrophage polarization plays a crucial role in regulating myocardial inflammation and injuries of coxsackievirus B3 (CVB3)-induced viral myocarditis (VM). It has been reported that miR-223 is a potent regulator of inflammatory responses that involved in macrophage polarization. However, the functional roles of miR-223 in CVB3-induced VM still remain unknown. Here, we found that miR-223 expression was significantly down-regulated in heart tissues and heart-infiltrating macrophages of CVB3-infected mice. Up-regulation of miR-223 in vivo protected the mice against CVB3-induced myocardial injuries characterized by the increased body weight and survival, enhanced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), relieved inflammation, depressed creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and aspartate transaminase (AST) levels, reduced production of interferon (IFN)-γ, interleukin (IL)− 6 as well as increased IL-10. We subsequently found that miR-233 up-regulation significantly suppressed the expression of M1 markers (iNOS, TNF-α and CD 86), and promoted the expression of M2 markers (Arginase-1, Fizz-1 and CD 206) in vivo and in vitro. Furthermore, we confirmed that miR-223 directly targeted Pknox1 to inhibit its expression, and the expression of Pknox1 was inversely correlated with miR-223 expression in heart tissues and heart-infiltrating macrophages of CVB3-infected mice. Gain-of-function analyses indicated that Pknox1 overexpression partially reversed the polarization phenotypes regulated by miR-223 overexpression. Taken together, the data suggest that miR-223 protects against CVB3-induced inflammation and myocardial damage, which may partly attribute to the regulation of macrophage polarization via targeting Pknox1. [ABSTRACT FROM AUTHOR]

Interleukin-17A (IL-17A) has been implicated in the pathogenesis of viral myocarditis (VMC). However, the role of IL-17A polymorphisms in susceptibility to VMC has not been reported to date. The aim of this study was to explore the association between IL-17A variants as well as serum IL-17 levels with VMC. Three single-nucleotide polymorphisms (SNPs) (rs2275913, rs3819025, and rs3748067) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in 236 VMC patients and 259 controls from China. Serum IL-17A levels were measured by enzyme-linked immunosorbent assay kits. Multivariable logistic regression analysis that the rs2275913 AA genotype and the haplotype -197A/+45G/+1249G (AGG) were associated with an increased risk of VMC (all P  < 0.05). Consistent with these findings, the rs2275913 AA genotype was linked to higher serum IL-17A compared to GG/AG genotype (all P  < 0.001). We observed no associations between the other two SNPs and risk of VMC. Serum IL-17A levels were significantly higher in the VMC group than controls ( P  < 0.001) and gradually increased with the increase of New York Heart Association grade in VMC patients ( P  < 0.05). Spearman correlation test revealed that the serum IL-17A level was correlated with the cardiac damage and left ventricular systolic functions among VMC patients (all P  < 0.05). Our study reveals that IL-17A expression may contribute to the development and severity of VMC. The SNP rs2275913 in the IL-17A gene might exert influence on susceptibility to VMC via linking with the serum IL-17A level. [ABSTRACT FROM AUTHOR]

Semaphorin7A (Sema7A) has been reported to play various roles in nerve axon growth, tumor suppression, and tissue remodeling, as well as regulation of intestinal inflammation diseases. Viral myocarditis (VMC) characterized by viral-myocardial-cell necrosis and inflammatory cell infiltration is a common clinical disease of the cardiovascular system. However, the role of Sema7A in coxsackievirus B3 (CVB3)-induced VMC has not been reported. In this study, we generated an acute VMC mouse model by CVB3 infection, and manipulated Sema7A expression by in vivo polyethyleneimine-mediated Sema7A down-regulation. Our results indicated that Sema7A was up-regulated in cardiomyocytes during VMC, and that Sema7A down-regulation following short hairpin RNA interference or mAb neutralization effectively protected mice from VMC. Additionally, reduced inflammatory responses were observed along with Sema7A down-regulation. Furthermore, adoptive transfer of α1β1-integrin macrophages exacerbated CVB3-induced myocarditis, suggesting the significance of α1β1-integrin macrophages in response to VMC. We observed that co-culture of neonatal myocardiocytes with macrophages increased the percentage of α1β1-integrin macrophages, while Sema7A neutralization reduced α1β1-integrin macrophages in heart tissue of VMC mice. These results demonstrated that Sema7A, as an inflammation regulator in CVB3-induced VMC, might interact with α1β1-integrin in macrophages to enhance the inflammatory response and aggravate disease severity. Our findings provided insight into the potential role of Sema7A as a therapeutic treatment for VMC. [ABSTRACT FROM AUTHOR]

Type B coxsackieviruses (CVB) can cause myocarditis and dilated cardiomyopathy (DCM), a potentially-fatal sequela that has been correlated to the persistence of viral RNA. Herein, we demonstrate that cardiac RNA persistence can be established even after an inapparent primary infection. Using an inducible Cre/lox mouse model, we ask: (i) Does persistent CVB3 RNA cause ongoing immune activation? (ii) If T1IFN signaling into cardiomyocytes is ablated after RNA persistence is established, is there any change in the abundance of persistent CVB3 RNA and/or does cytopathic infectious virus re-emerge? (iii) Does this loss of T1IFN responsiveness by cardiomyocytes lead to the recurrence/exacerbation of myocarditis? Our findings suggest that persistent enteroviral RNAs probably do not contribute to ongoing myocardial disease, and are more likely to be the fading remnants of a recent, possibly sub-clinical, primary infection which may have set in motion the process that ultimately ends in DCM. [ABSTRACT FROM AUTHOR]

1,25-dihydroxyvitamin D 3 and its analog (paricalcitol) have beneficial effects on multiple systems and diseases, including myocarditis. However, the therapeutic effect of cholecalciterol cholesterol emulsion (CCE) on myocarditis and the role of pyroptosis in the progress of myocarditis have not been determined. The objective of this study was to investigate the effect of CCE on experimental autoimmune myocarditis and its underlying mechanisms. The ratio of heart weight to body weight was decreased after CCE treatment compared with vehicle-treated controls. In addition, CCE improved the general status of mice, suppressed myocardial apoptosis, and inhibited the pyroptosis signaling pathway. Therefore, CCE can ameliorate experimental autoimmune myocarditis by downregulating the pyroptosis signaling pathway. [ABSTRACT FROM AUTHOR]

Myocarditis is an inflammatory disease of the myocardium associated with immune dysfunction which may frequently lead to the development of dilated cardiomyopathy. Experimental autoimmune myocarditis is an animal model which mimics myocarditis in order to allow assessment of the therapeutic effects of different molecules on this disease. We aimed to review the inflammatory and immunological mechanisms involved in the pathogenesis of the myocarditis and finding natural products and phytochemicals with anti-myocarditis activities based on studies of cardiac myosin-induced experimental autoimmune myocarditis in rodents. A number of natural molecules (e.g. apigenin, berberine and quercetin) along with some plant extracts were found to be effective in alleviating experimental autoimmune myocarditis. Upregulation of Th1-type cytokines and elevation of the Th2-type cytokines (IL-4 and IL-10), mitigation of oxidative stress, modulation of mitogen-activated protein kinase signaling pathways and increasing Sarco-endoplasmic reticulum Ca 2+ -ATPase levels are among the most important anti-myocarditis mechanisms for the retrieved molecules and extracts. Interestingly, there are structural similarities between the anti-EAM compounds, suggesting the presence of similar pharmacophore and enzymatic targets for these molecules. Naturally occurring molecules discussed in the present article are potential anti-myocarditis drugs and future additional animal studies and clinical trials would shed more light on their effectiveness in the treatment of myocarditis and prevention of dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Viral myocarditis is a leading cause of sudden death in young adults as the limited turnover of cardiac myocytes renders the heart particularly vulnerable to viral damage. Viruses induce an antiviral type I interferon (IFN-α/β) response in essentially all cell types, providing an immediate innate protection. Cardiac myocytes express high basal levels of IFN-β to help pre-arm them against viral infections, however the mechanism underlying this expression remains unclear. Using primary cultures of murine cardiac and skeletal muscle cells, we demonstrate here that the mitochondrial antiviral signaling (MAVS) pathway is spontaneously activated in unstimulated cardiac myocytes but not cardiac fibroblasts or skeletal muscle cells. Results suggest that MAVS association with the mitochondrial-associated ER membranes (MAM) is a determinant of high basal IFN-β expression, and demonstrate that MAVS is essential for spontaneous high basal expression of IFN-β in cardiac myocytes and the heart. Together, results provide the first mechanism for spontaneous high expression of the antiviral cytokine IFN-β in a poorly replenished and essential cell type. [ABSTRACT FROM AUTHOR]

Sphingosine 1-phosphate (S1P), via binding to its specific receptors of S1PR1, participates in the regulation of both innate and adaptive immunity. Recent reports have identified S1P as a messenger mediating inflammation. However, roles of S1P in Coxsackievirus B3 (CVB3)-induced myocarditis were largely unknown. Here, we investigated the effect of S1P treatment on CVB3-induced myocarditis in vivo. We found that CVB3 infection downregulated S1PR1 expression in spleen and decreased the proportion of invariant natural killer T cells (iNKT) in CD3 positive T cells both in spleen and in blood from left ventricle, which accompanied by severe inflammation lesions and more virus capsid protein (VP1) expression in heart tissue. In comparison, S1P supply upregulated iNKT in the spleen and in blood from left ventricle, which represented the strengthening of anti-inflammatory effects. Indeed, inflammation infiltration, VP1 expression and apoptosis in the myocardium was all downregulated. These results demonstrated that S1P supplement could alleviate CVB3-induced myocarditis. [ABSTRACT FROM AUTHOR]

The extensive, diverse communities that constitute the microbiome are increasingly appreciated as important regulators of human health and disease through inflammatory, immune, and metabolic pathways. We sought to elucidate pathways by which microbiota contribute to inflammatory, autoimmune cardiac disease. We employed an animal model of experimental autoimmune myocarditis (EAM), which results in inflammatory and autoimmune pathophysiology and subsequent maladaptive cardiac remodeling and heart failure. Antibiotic dysbiosis protected mice from EAM and fibrotic cardiac dysfunction. Additionally, mice derived from different sources with different microbiome colonization profiles demonstrated variable susceptibility to disease. Unexpectedly, it did not track with segmented filamentous bacteria (SFB)-driven Th17 programming of CD4 + T cells in the steady-state gut. Instead, we found disease susceptibility to track with presence of type 3 innate lymphoid cells (ILC3s). Ablating ILCs by antibody depletion or genetic tools in adoptive transfer variants of the EAM model demonstrated that ILCs and microbiome profiles contributed to the induction of CCL20/CCR6-mediated inflammatory chemotaxis to the diseased heart. From these data, we conclude that sensing of the microbiome by ILCs is an important checkpoint in the development of inflammatory cardiac disease processes through their ability to elicit cardiotropic chemotaxis. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) have attracted widespread attention as an emerging environmental pollutant. Especially in aquatic ecosystems, the harm of MPs to aquatic animals has increasingly become a severe environmental problem. In this study, we constructed a carp polystyrene microplastics (PS-MPs) exposure model to explore the damage and mechanism of PS-MPs exposure to carp myocardial tissue. The results of H&E, TUNEL, and AO/EB staining showed that PS-MPs exposure could induce inflammation, apoptosis, and necrosis in carp myocardial tissue and cardiomyocytes. In addition, our study explored the targeting relationship between PS-MPs and TLR4 and found that PS-MPs exposure could significantly increase the expression of TLR4 pathway-related factors. As the concentration of PS-MPs increased, the NF-κB pathway and inflammation-related factors increased dose-dependent. In addition, myocardial injury induced by exposure to PS-MPs was predominantly apoptotic, accompanied by necrosis. In short, our data suggest that PS-MPs cause damage to myocardial tissue via the TLR4\NF-κB pathway. The above findings enrich the theory of toxicological studies on PS-MPs and provide an essential reference for aquaculture. [Display omitted] • PS-MPs can cause myocardium inflammation of carp. • PS-MPs can cause myocardium inflammation of carp. • PS-MPs can activate TLR4 signaling pathway. • PS-MPs can activate NF-κB pathway. [ABSTRACT FROM AUTHOR]

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. In investigating concerns brought up regarding the authenticity of the article, the editors reached out to the corresponding author for an explanation. The corresponding author failed to provide a satisfactory explanation. The editors therefore feel that the findings of the manuscript cannot be relied upon and that the article needs to be retracted. [ABSTRACT FROM AUTHOR]

Although Schistosoma species and Trypanosoma cruzi share common endemic areas, co-infections by these parasites remains overlooked. By using a murine model of S. mansoni and T. cruzi co-infection, we investigated if and to what extent these infections might interact to change the pathological outcomes typically observed when the host is infected by a single parasite species. Swiss mice were randomized into four groups: uninfected (NI) and those infected by S. mansoni (SM), T. cruzi (TC) or co-infected (SM + TC). After 120 days of S. mansoni infection, T. cruzi was concurrently inoculated and the infection occurred for 30 days. Taken together, we identified that the overlap of Th2 (schistosomiasis) and Th1 (Chagas disease) immunological patterns changes the host resistance against both pathogens. Beyond impairing the control of granulomatous inflammation, T. cruzi parasitemia and parasitism in co-infected animals, the Th2 inflammatory response against S. mansoni elicits the activation of the arginase-1 pathway to the detriment of inducible oxide nitric synthase (iNOS) expression and nitric oxide (NO) production, contributing to the liver damage, with minor effects on heart pathology. [ABSTRACT FROM AUTHOR]

Myocarditis, the principal cause of dilated cardiomyopathy and heart failure in young adults, is associated with autoimmunity to human cardiac α-myosin (hCAM) and the DR4 allele of human major histocompatibility II (MHCII). We developed an hCAM-induced myocarditis model in human HLA-DR4 transgenic mice that lack all mouse MHCII genes, demonstrating that immunization for 3 weeks significantly increased splenic T-cell proliferative responses and titres of IgG1 and IgG2c antibodies, abolished weight gain, provoked cardiac inflammation and significantly impaired cardiac output and fractional shortening, by echocardiography, compared to adjuvant-injected mice. Neither cardiac dilatation nor fibrosis occurred at this time point but prolonging the experiment was associated with mortality. Treatment with mixtures of hCAM derived peptides predicted to have high affinity for DR4 significantly preserved ejection fraction and fractional shortening. Our new humanized mouse model of autoimmune cardiomyopathy should be useful to refine hCAM-derived peptide treatment. [ABSTRACT FROM AUTHOR]

Backgroud Macrophages are important mediators in inflammatory cardiovascular diseases. Experimental autoimmune myocarditis (EAM) is characterized by pronounced macrophages infiltration, cardiac necrosis and cardiac fibrosis. Androgen receptor (AR) is a regulator of immune system which can control macrophages' infiltration and function in various inflammatory-related diseases. However, the effect of AR on the inflammatory response in EAM is unknown. Our study aims to investigate the potential role of AR on the development of autoimmune myocarditis. Methods and results In our study, we found that AR was increased in the myocardium and was associated with the time-course of EAM progression, which motivated us to use ASC-J9 (an enhancer of AR degradation). The results revealed that ASC-J9 administration in EAM mice resulted in an attenuation in the severity of disease and cardiac injury, a reduced CD4 + T cell response, reduced monocyte/macrophage infiltration, and decreases in the pro-inflammatory cytokines. Furthermore, ASC-J9 was also found to prevent Raw264.7 cells polarization to M1 macrophages in response to LPS by upregulating suppressor of cytokine signaling 1(SOCS1) and downregulating signal transducer and activator of the transcription 5(STAT5) activity. Conclusions AR facilitated EAM development, and targeting AR with ASC-J9 attenuated cardiac injury and dysfunction by inhibiting macrophages polarization towards M1 macrophages. [ABSTRACT FROM AUTHOR]

Viral myocarditis (VMC) is closely related to apoptosis, oxidative stress, innate immunity, and energy metabolism, which are all linked to mitochondrial dysfunction. A close nexus between mitochondrial dynamics and cardiovascular disease with mitochondrial dysfunction has been deeply researched, but there is still no relevant report in viral myocarditis. In this study, we aimed to explore the role of Dynamin-related protein 1 (Drp1)-linked mitochondrial fission in VMC. Mice were inoculated with the Coxsackievirus B3 (CVB3) and treated with mdivi1 (a Drp1 inhibitor). Protein expression of Drp1 was increased in mitochondria while decreased in cytoplasm and accompanied by excessive mitochondrial fission in VMC mice. In addition, midivi1 treatment attenuate inflammatory cells infiltration in myocardium of the mice, serum Cardiac troponin I (CTnI) and Creatine kinase-MB (CK-MB) level. Mdivi1 also could improved the survival rate of mice and mitochondrial dysfunction reflected as the up-regulated mitochondrial marker enzymatic activities of succinate dehydrogenase (SDH), cytochrome c oxidase (COX) and mitochondrial membrane potential (MMP). At the same time, mdivi1 rescued the body weight loss, myocardial injury and apoptosis of cardiomyocyte. Furthermore, decease in LVEDs and increase in EF and FS were detected by echocardiogram, which indicated the improved myocardial function. Thus, Drp1-linked excessive mitochondrial fission contributed to VMC and midivi1 may be a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

Viral myocarditis is the inflammation caused by myocardial virus infection, and the coxsackievirus group B3 virus (CVB3) is the most common pathogen. An efficient therapeutic agent against viral myocarditis is currently unavailable. IL-33, a new member of the IL-1 cytokine superfamily, exhibits potential immunotherapeutic effect against inflammatory and autoimmune diseases. However, the functional role of IL-33 in viral myocarditis has not been investigated. To examine the therapeutic role of IL-33 in viral myocarditis, an IL-33 overexpression plasmid (pDisplay-IL-33) and IL-33 knockdown plasmid (pLL3.7-IL-33) were packaged with polyethylenimine and delivered intravenously at the orbital area of BALB/c male mice after CVB3 infection. Then, myocarditis severity was assessed 7 days after infection. Results showed that IL-33 up-regulation significantly alleviated the severity of viral myocarditis with an increased cardiac contractive function and survival rate. Mechanistic studies demonstrated that IL-33 can stimulate ST2L + F4/80 + macrophages and ST2L + CD4 + T cells in cardiac tissue to express IL-4, which is a potent inducer for macrophage M2 polarization. Mice with adoptive transfer of M2 macrophages exhibited less cardiac inflammation and attenuated myocarditis, suggesting the protective role of M2 macrophage in viral myocarditis. Additionally, IL-4 neutralization abolished the IL-33-mediated cardiac functional improvement in myocarditis mice. Collectively, our findings provide a novel therapeutic role for IL-33 in CVB3-induced myocarditis. [ABSTRACT FROM AUTHOR]

Viral myocarditis is common and can progress to cardiac failure. Cardiac cell pro-inflammatory responses are critical for viral clearance, however sustained inflammatory responses contribute to cardiac damage. The transcription factor NF-κB regulates expression of many pro-inflammatory cytokines, but basal and induced activation of NF-κB in different cardiac cell types have not been compared. Here, we used primary cultures of cardiac myocytes and cardiac fibroblasts to identify cardiac cell type-specific events. We show that while viral infection readily stimulates activation of NF-κB in cardiac fibroblasts, cardiac myocytes are largely recalcitrant to activation of NF-κB. Moreover, we show that cardiac myocyte subpopulations differ in their NF-κB subcellular localization and identify the cis -Golgi as a cardiac myocyte-specific host compartment. Together, results indicate that NF-κB-dependent signaling in the heart is cardiac cell type-specific, likely reflecting mechanisms that have evolved to balance responses that can be either protective or damaging to the heart. [ABSTRACT FROM AUTHOR]

In myocarditis and dilated cardiomyopathy (DCM) patients the immune system may play an important role in disease progression. In this study, we aimed to identify new antigens as a target for autoimmune response that might play a crucial role in these diseases. Therefore, a peptide-array was used to investigate antibody binding profiles in patients with autoimmune myocarditis or DCM compared to healthy controls and thus to identify disease relevant antigens. To analyze the pathogenicity of the identified antigens, an experimental autoimmune myocarditis (EAM) model was used. Hereby, 3 peptide sequences, derived from myosin-binding-protein-C (MYBPC) fast-type, RNA-binding-protein 20 (RBM20), and dystrophin, showed pathogenic effects on the myocardium of mice. In summary, 3 potentially cardiopathogenic peptides (MYBPC fast-type, RBM20, dystrophin) were identified. Thus, this study could serve as a basis for future investigations aimed at determining further antigens leading to pathogenic effects on the myocardium of DCM as well as myocarditis patients. [ABSTRACT FROM AUTHOR]

Viral myocarditis (VMC) is characterized as an inflammatory process of the myocardium and can be fatal in infants and children. Melittin is a major polypeptide in honey bee venom that has been traditionally used against inflammation. However, its effect on VMC and the underlying molecular mechanism has not been reported. In this study, BALB/c mice were intraperitoneally injected with CVB3 to build a VMC model and treated with melittin. The results showed that melittin increased the mice's body weight and inhibited CVB3 replication. HE staining also showed that melittin alleviated myocardial injury in the VMC model. Flow cytometry showed that melittin inhibited myocardial cell apoptosis; in addition, real-time PCR showed that melittin decreased the expression of bax and caspase-3, and increased the expression of bcl-2. The results of echocardiographic examination showed that melittin improved cardiac function. Moreover, melittin decreased the activity of AST, CK, HBDH and LDH, and decreased the production of IL-1β, IL-6, TNF-α and MCP-1 in CVB3-induced myocardial tissues. Finally, we also found that melittin increased the expression of HDAC2 and activated the GSK-3β/Nrf2/ARE signaling pathway, whereas these changes were reversed by inhibition of HDAC2 in VMC model mice. In conclusion, our results suggested that melittin ameliorates CVB3-induced myocarditis via activation of the HDAC2-mediated GSK-3β/Nrf2/ARE signaling pathway. [ABSTRACT FROM AUTHOR]

The immunoproteasome is an inducible host mechanism that aids in the clearance of damaged proteins. The immunoproteasome also influences immune function by enhancing peptide presentation by MHC class I and promotes inflammation via IκB degradation and activation of NF-κB. We used mouse adenovirus type 1 (MAV-1) to characterize the role of the immunoproteasome in adenovirus pathogenesis. Following intranasal infection of mice, immunoproteasome activity in the heart and lung was significantly increased in an IFN-γ-dependent manner. Absence of the β5i immunoproteasome subunit and pharmacological inhibition of β5i activity had minimal effects on viral replication, virus-induced cellular inflammation, or induction of cytokine expression. Likewise, the establishment of protective immunity following primary infection was not significantly altered by β5i deficiency. Thus, although immunoproteasome activity is robustly induced during acute infection with MAV-1, our data suggest that other mechanisms are capable of compensating for immunoproteasome activity to maintain antiviral immunity and appropriate inflammatory responses. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is the most serious complication of chronic Chagas disease, caused by infection with the protozoan Trypanosoma cruzi. Exacerbated inflammation of the myocardium constitutes a major pathologic component of the disease. In the myocardial microenvironment, parasite antigens and host inflammatory mediators may aggravate tissue damage. The glycoinositolphospholipid (GIPL) from T. cruzi is an inflammation-eliciting antigen recognized by Toll-like receptor 4 (TLR4), whereas the proinflammatory cytokine macrophage migration inhibitory factor (MIF) promotes progression of chronic Chagas cardiomyopathy. We herein aimed to examine the involvement of GIPL and MIF in molecular mechanisms leading to a pathogenic inflammatory response in HL-1 cardiomyocytes and HMEC microvascular endothelial cells. Immunofluorescence analysis revealed that GIPL enhanced TLR4 expression in both cell types. We found that TLR4/GIPL interaction and MIF activity modulated the arachidonic acid pathway implicated in persistent inflammation. The combination of GIPL at 50 μg/ml and MIF at 50 ng/ml upregulated type 2 cyclooxygenase (COX-2) levels in HL-1 and HMEC cells, in a stronger way than each molecule acting independently. Moreover, increased expression of prostanoid synthases and release of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) were detected in stimulated cells. Transfection experiments in HL-1 and HMEC cells showed that COX-2 induction was transcriptionally regulated through GIPL-TLR4 engagement and NFκB signaling cascade. (GIPL + MIF)-triggered NFκB activation was markedly attenuated by treatment with 100 μM Fenofibrate, a PPAR-α ligand. Fenofibrate reduced COX-2-dependent generation of bioactive lipids in HL-1 and HMEC cells. In addition, Fenofibrate abolished (GIPL + MIF)-fostered release of NO, IL-1β, IL-6, TNF-α, and CCL2. The combined actions of GIPL and MIF display potential for amplifying the inflammatory response in myocardium of parasite-infected hosts. Our current findings might help develop more effective measures to ameliorate cardiovascular abnormalities associated with Chagas heart disease. • T. cruzi GIPL cooperates with MIF to induce eicosanoid production in cardiac cells. • NFκB mediates (GIPL + MIF)-triggered proinflammatory effects. • GIPL upregulates TLR4 expression in cardiomyocyte and vascular endothelial cell lines. • Fenofibrate inhibits (GIPL + MIF)-driven release of inflammatory mediators. [ABSTRACT FROM AUTHOR]

The present study aimed to explore the pathogenesis of autoimmune myocarditis induced by PD-1 inhibitors and their potential therapeutic targets. Mouse models of autoimmune myocarditis induced by PD-1 inhibitor in mouse models of polymyositis were established. The expression level of PD-1 and regulatory T cells (Tregs), CD4, CD8 + T cells, inflammation, apoptosis and autophagy-related factors, including IL-6, TGF-β, AMA-M2, Fas/FasL, LC3 and p62 were detected in peripheral blood , muscle or myocardium of mice in each group, using ELISA, RT-PCR, Western Blot and immunofluorescence. In addition, HE and TUNEL staining and ultrastructural scanning were performed on the myocardium of mice in each group. Results showed that the expression level of PD-1 in the two myositis groups was significantly lower than that in the control group, and the level of PD-1 was lower in the myocarditis group than that in the polymyositis group. In the myocardium, TGF-β, p62, and Tregs proportion showed the same expression level trend as PD-1, while CD8, IL-6, IL-10 and LC3 showed the opposite trend. Levels of Fas/FasL were significantly higher in both myositis groups, but were slightly lower in the myocarditis group, as was AMA-M2. Inflammation, apoptosis, and autophagy were observed in both myositis groups, but were more severe in the myocarditis group. In summary, the decreased expression level of PD-1 leads to decreased Tregs level in the myocardium, aggravated inflammatory response, apoptosis and autophagy, which may be the pathological mechanism of myocarditis induced by PD-1 inhibitors. [ABSTRACT FROM AUTHOR]