Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis

Zhong, Danli; Wu, Caimei; Bai, Jingjing; Xu, Duanfu; Zeng, Xiaofeng; Wang, Qian

doi:10.7717/peerj.8611

Cited by 11 publications

(7 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 Emerging evidence from IFN type 1-driven autoimmune diseases such as systemic lupus erythematosus (SLE) and JDM, and rare monogenic type 1 interferonopathies, suggest that there is a relationship between mitochondrial dysfunction, inappropriate production of ROS and IFN-driven disease pathology. [20][21][22][23][24][25] However, the mechanisms underlying this association remain ill-defined.…”

Section: Myositismentioning

confidence: 99%

“…[47][48][49] However, gene expression modules associated with mitochondrial dysfunction and IFN type 1 have also been identified in JDM bulk muscle, the inflammatory site of the disease. 23 A study in adult dermatomyositis showed a correlation between mitochondrial dysfunction and IFN type 1, and using an experimental autoimmune mouse model identified that NAC prevented mitochondrial dysfunction, IFN type I transcript and muscle weakness. 50 Studies have also demonstrated that single nucleotide polymorphisms or altered copy number within mtDNA are associated with the development of adult idiopathic inflammatory myopathies.…”

Section: Myositismentioning

confidence: 99%

See 1 more Smart Citation

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

Wilkinson¹,

Moulding

McDonnell

et al. 2022

Ann Rheum Dis

View full text Add to dashboard Cite

ObjectivesTo define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).MethodsRNA-sequencing was performed on CD4+, CD8+, CD14+and CD19+cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/orn-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35.ResultsDysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including ‘megamitochondria’, cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC.ConclusionsThese results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.

show abstract

Section: Myositismentioning

confidence: 99%

Section: Myositismentioning

confidence: 99%

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

Wilkinson¹,

Moulding

McDonnell

et al. 2022

Ann Rheum Dis

View full text Add to dashboard Cite

show abstract

“…There is evidence that the mitochondrial dysfunction has an important role in the pathophysiology of DM. The patients with DM have a reduced maximal aerobic capacity [ 9 , 10 ], which is inversely correlated with the proportion of COX deficient muscle fibres and mitochondrial functional defects are considered a hallmark of DM [ 5 , 11 ]. The exact mechanism for the mitochondrial dysfunction has not been clarified and there may be several mechanisms involved.…”

Section: Introductionmentioning

confidence: 99%

Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion

Hedberg‐Oldfors

Lindgren

Visuttijai

et al. 2022

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

Aims Patients with dermatomyositis (DM) suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in DM. Methods Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with DM were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridisation, next generation deep sequencing and quantitative polymerase chain reaction (PCR). Results There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridisation of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. Conclusion The respiratory chain dysfunction in DM muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA, is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.

show abstract

“…Weighted gene co-expression network analysis (WGCNA) is an algorithm for detecting correlation between genes ( Langfelder & Horvath, 2008 ; Langfelder & Horvath, 2012 ), which facilitates network-based genetic screening methods and is helpful to uncover potential biomarkers and therapeutic targets for diseases. WGCNA has been successfully practiced in studies of autoimmune diseases, such as juvenile dermatomyositis ( Zhong et al, 2020 ), lupus nephritis ( Yang & Li, 2019 ), ulcerative colitis ( Zhang et al, 2020 ) and Sjögren’s syndrome ( Yao et al, 2019 ). We integrated multiple bioinformatics methods to analyze microarray datasets derived from the Gene Expression Omnibus (GEO) repository and validated the data mining results in three ways in order to identify diagnostic genes and transcriptional regulators of RA.…”

Section: Introductionmentioning

confidence: 99%

Identification of diagnostic genes and vital microRNAs involved in rheumatoid arthritis: based on data mining and experimental verification

Ren

Zheng

et al. 2021

PeerJ

View full text Add to dashboard Cite

Background The pathogenesis of rheumatoid arthritis (RA) is complex. This study aimed to identify diagnostic biomarkers and transcriptional regulators that underlie RA based on bioinformatics analysis and experimental verification. Material and Methods We applied weighted gene co-expression network analysis (WGCNA) to analyze dataset GSE55457 and obtained the key module most relevant to the RA phenotype. We then conducted gene function annotation, gene set enrichment analysis (GSEA) and immunocytes quantitative analysis (CIBERSORT). Moreover, the intersection of differentially expressed genes (DEGs) and genes within the key module were entered into the STRING database to construct an interaction network and to mine hub genes. We predicted microRNA (miRNA) using a web-based tool (miRDB). Finally, hub genes and vital miRNAs were validated with independent GEO datasets, RT-qPCR and Western blot. Results A total of 367 DEGs were characterized by differential expression analysis. The WGCNA method divided genes into 14 modules, and we focused on the turquoise module containing 845 genes. Gene function annotation and GSEA suggested that immune response and inflammatory signaling pathways are the molecular mechanisms behind RA. Nine hub genes were screened from the network and seven vital regulators were obtained using miRNA prediction. CIBERSORT analysis identified five cell types enriched in RA samples, which were closely related to the expression of hub genes. Through ROC curve and RT-qPCR validation, we confirmed five genes that were specific for RA, including CCL25, CXCL9, CXCL10, CXCL11, and CXCL13. Moreover, we selected a representative gene (CXCL10) for Western blot validation. Vital miRNAs verification showed that only the differences in has-miR-573 and has-miR-34a were statistically significant. Conclusion Our study reveals diagnostic genes and vital microRNAs highly related to RA, which could help improve our understanding of the molecular mechanisms underlying the disorder and provide theoretical support for the future exploration of innovative therapeutic approaches.

show abstract

Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis

Cited by 11 publications

References 48 publications

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion

Identification of diagnostic genes and vital microRNAs involved in rheumatoid arthritis: based on data mining and experimental verification

Contact Info

Product

Resources

About