Fibrinogen‐like protein‐2 causes deterioration in cardiac function in experimental autoimmune myocarditis rats through regulation of programmed death‐1 and inflammatory cytokines

Zhang, Zheng; Yu, Yong‐Sen; Potla, Ratnakar; Wu, Yujing; Wu, Hao

doi:10.1111/imm.12837

Cited by 14 publications

(11 citation statements)

References 21 publications

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“…Elevated levels of Ch3L1 and sCD14 have been identified as promising immunomarkers in CSF samples from children with inflammatory disorders ( 23 ). The assembly of proteins relevant in inflammation also includes C-reactive protein, zinc-alpha-2-glycoprotein, neural cell adhesion molecule 2 ( 24 ), vitamin D-binding protein ( 25 ), fibrinogen-like protein 1 ( 26 , 27 ), and hepatocyte growth factor activator ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Surrogate Cerebrospinal Fluid Biomarkers for Assessing the Efficacy of Gene Therapy in Hurler Syndrome

et al. 2021

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Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydroxylase alpha-l-iduronidase (IDUA). The resulting accumulation of dermatan and heparan sulfate induces intellectual disabilities and pre-mature death, and only a few treatment options are available. In a previous study, we demonstrated the feasibility, safety, and efficacy of gene therapy by injecting recombinant adeno-associated viral vector serotype (AAV)2/5-IDUA into the brain of a canine model of MPS I. We report on a quantitative proteomic analysis of control dogs and untreated dogs with MPS I cerebrospinal fluid (CSF) that had been collected throughout the study in the MPS I dogs. Mass spectrometry (MS) analysis identified numerous proteins present at altered levels in MPS I CSF samples. Quantitative immunoblotting, performed on CSF from healthy controls, untreated MPS I dogs, and MPS I dogs early treated and late treated by gene therapy, confirmed the MS data for a subset of proteins with higher abundance (neuronal pentraxin 1, chitinase 3-like 1, monocyte differentiation antigen CD14, and insulin-like growth factor-binding protein 2). Scoring of the results shows that the expression levels of these proteins are close to those of the control group for dogs that underwent gene therapy early in life but not for older treated animals. Our results disclose four novel predictive biomarker candidates that might be valuable in monitoring the course of the neurological disease in MPS patients at diagnosis, during clinical follow-up, and after treatment.

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Section: Discussionmentioning

confidence: 99%

Surrogate Cerebrospinal Fluid Biomarkers for Assessing the Efficacy of Gene Therapy in Hurler Syndrome

et al. 2021

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“…Twelve mice were injected with an equal volume of PBS as control. The miR-141-3p agomir, short hairpin (sh)RNA targeting STAT4 (sh-STAT4) lentivirus, STAT4 overexpression lentivirus, or their controls [agomir-NC and sh-negative control (NC)] were purchased from Shanghai Genechem (Shanghai, China) and administered to the mice via the tail vein (1 mL/mouse) at a concentration of 5 ϫ 10 7 TU/mL on the 1st day postmodeling (31). At day 0 and 7 after model establishment, dimethyl sulfoxide (DMSO) (3176; Tocris Bioscience, Abingdon, UK) and Tofacitinib (CP-690550; Pfizer, New York, NY) were intraperitoneally injected into mice at a dose of 30 mg•kg Ϫ1 •time Ϫ1 (6).…”

Section: Methodsmentioning

confidence: 99%

“…At day 0 and 7 after model establishment, dimethyl sulfoxide (DMSO) (3176; Tocris Bioscience, Abingdon, UK) and Tofacitinib (CP-690550; Pfizer, New York, NY) were intraperitoneally injected into mice at a dose of 30 mg•kg Ϫ1 •time Ϫ1 (6). The diet, activity, and mental state of the mice were analyzed every day, with the weight of the mice measured at regular intervals (31).…”

Section: Methodsmentioning

confidence: 99%

“…A diasonograph (Philips, Andover, MA) was next used to detect the ultrasonic cardiogram of each mouse at a transducer frequency of 37 MHz. The indexes for detection included left ventricular end-diastolic dimension (LVEDd), left ventricular end-systolic transverse diameter (LVEDs), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and heart rate (HR) (31). Each measurement was repeated three times.…”

Section: Methodsmentioning

confidence: 99%

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

Pan

Tan

Wang

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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“…Similarly, increased expressions of Lyz2, a chemotactic for neutrophils; and Ccl6, a chemokine expressed by neutrophil and macrophage lineages 25 were seen in Ccl6 + cluster 0. In addition, Fgl2, a regulator of immune and inflammatory responses 62 ; and Itgax or CD11c, a marker of DCs that triggers respiratory burst in neutrophils, were found in Gm2a + cluster 1 (Fig 6C). Interestingly, cluster 3 neutrophils contained genes involved in the regulation of inflammation via inhibition of NF-kB, including Nfkbia, Nfkbie, Tnfaip3, and Tnf.…”

Section: Fig 5e and Figmentioning

confidence: 96%

Dissecting the Cellular Landscape and Transcriptome Network in Viral Myocarditis by Single-Cell RNA Sequencing

Lasrado

Borcherding

Arumugam

et al. 2021

Preprint

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Myocarditis induced with Coxsackievirus B3 (CVB3) is commonly employed to study viral pathogenesis in mice. Although infectious virus is cleared after the acute phase, affected animals chronically develop the features of dilated cardiomyopathy, which may involve the mediation of immune and non-immune cells. To dissect this complexity, we performed single-cell RNA sequencing on heart cells obtained from healthy and myocarditic mice, leading us to note that myocarditic mice had significantly higher proportions of myeloid cells, CD4 and CD8 T cells, and fibroblasts, whereas NK cells, ILCs and B cells were low. While the transcriptome profiles of myeloid cells revealed detection of monocytes and macrophages of M2 phenotype with pathways important in immune metabolism and inflammation, T cells consisted of Th17 cells, CTLs, and Treg cells with transcriptome signatures critical for cytotoxic functions. Although fibroblasts detected in myocarditic mice were phenotypically heterogeneous, their transcriptomes played roles in fibrosis and regulation of inflammation and immune responses. Additionally, analysis of intercellular communication networks revealed unique interactions and signaling pathways in the cardiac cellulome, whereas myeloid cells and T cells in myocarditic mice revealed uniquely upregulated transcription factors modulating cardiac remodeling functions. Taken together, our data suggest that M2 cells, T cells, and fibroblasts may cooperatively or independently participate in the pathogenesis of viral myocarditis.

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Fibrinogen‐like protein‐2 causes deterioration in cardiac function in experimental autoimmune myocarditis rats through regulation of programmed death‐1 and inflammatory cytokines

Cited by 14 publications

References 21 publications

Surrogate Cerebrospinal Fluid Biomarkers for Assessing the Efficacy of Gene Therapy in Hurler Syndrome

Surrogate Cerebrospinal Fluid Biomarkers for Assessing the Efficacy of Gene Therapy in Hurler Syndrome

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

Dissecting the Cellular Landscape and Transcriptome Network in Viral Myocarditis by Single-Cell RNA Sequencing

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