miR-23a contributes to T cellular redox metabolism in juvenile idiopathic oligoarthritis

Rajendiran, Anandhi; Klemm, Patricia; Schippers, Angela; Scheufen, Anja; Schwarz, Tobias; Peitz, Joachim; Brandenburg, Lars‐Ove; Wagner, Norbert; Consolaro, Alessandro; Raggi, Federica; Bosco, Maria Carla; Luedde, Tom; Foell, Dirk; Denecke, Bernd; Horneff, Gerd; Ohl, Kim; Tenbrock, Klaus

doi:10.1093/rheumatology/keab709

Cited by 6 publications

(14 citation statements)

References 32 publications

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“…The finding that an elevated number of EV-prots were differentially or exclusively expressed in SF vs matched PL samples from newly-diagnosed OJIA patients probably reflect the enrichment of distinct EV populations endowed with specific biologic functions or of distinct nature ( 29 , 65 ) related to the diverse cellular composition in the joints respect to the circulation. These results are in line with our previous findings demonstrating different microRNAs patterns in EVs released in, and mononuclear cells from, SF and PB samples of new-onset OJIA patients ( 45 , 66 ), suggesting specific fingerprints of joint disease.…”

Section: Discussionsupporting

confidence: 93%

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers

et al. 2023

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IntroductionNew early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients.MethodsFourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples.ResultsWe first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups.DiscussionThese data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease.

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Section: Discussionsupporting

confidence: 93%

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers

et al. 2023

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“…This is manifested in high uptakes of glucose ( Figure 1 A) and fatty acids ( Figure 1 B,C), a greater mitochondrial mass ( Figure 1 D), and a higher neutral lipid content ( Figure 1 E,F). In addition, we recently showed higher mitochondrial ROS [ 37 ], and a higher overall abundance of ROS in SF T cells [ 37 ]. The metabolic and inflammatory activation to which T cells are exposed in inflamed joints can be mimicked in HC T cells by incubation with SF [ 35 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…In addition, we recently showed higher mitochondrial ROS [ 37 ], and a higher overall abundance of ROS in SF T cells [ 37 ]. The metabolic and inflammatory activation to which T cells are exposed in inflamed joints can be mimicked in HC T cells by incubation with SF [ 35 , 37 ]. In detail, the effects of SF incubation include a higher secretion of IFN-γ and IL17a, enhanced T cell proliferation, raised mitochondrial ROS as well as higher overall ROS production, and phosphorylation of mTOR [ 35 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…The metabolic and inflammatory activation to which T cells are exposed in inflamed joints can be mimicked in HC T cells by incubation with SF [ 35 , 37 ]. In detail, the effects of SF incubation include a higher secretion of IFN-γ and IL17a, enhanced T cell proliferation, raised mitochondrial ROS as well as higher overall ROS production, and phosphorylation of mTOR [ 35 , 37 ]. In addition, we found a greater mitochondrial mass after incubation of HC T cells with SF ( Figure 1 G,H).…”

Section: Resultsmentioning

confidence: 99%

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NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA

et al. 2022

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Background: CD4+ T cells critically contribute to the initiation and perturbation of inflammation. When CD4+ T cells enter inflamed tissues, they adapt to hypoxia and oxidative stress conditions, and to a reduction in nutrients. We aimed to investigate how this distinct environment regulates T cell responses within the inflamed joints of patients with childhood rheumatism (JIA) by analyzing the behavior of NRF2—the key regulator of the anti-oxidative stress response—and its signaling pathways. Methods: Flow cytometry and quantitative RT-PCR were used to perform metabolic profiling of T cells and to measure the production of inflammatory cytokines. Loss of function analyses were carried out by means of siRNA transfection experiments. NRF2 activation was induced by treatment with 4-octyl-Itaconate (4-OI). Results: Flow cytometry analyses revealed a high metabolic status in CD4+ T cells taken from synovial fluid (SF) with greater mitochondrial mass, and increased glucose and fatty acid uptake. This resulted in a heightened oxidative status of SF CD4+ T cells. Despite raised ROS levels, expression of NRF2 and its target gene NQO1 were lower in CD4+ T cells from SF than in those from blood. Indeed, NRF2 activation of CD4+ T cells downregulated oxidative stress markers, altered the metabolic phenotype and reduced secretion of IFN-γ. Conclusion: NRF2 could be a potential regulator in CD4+ T cells during chronic inflammation and could instigate a drift toward disease progression or regression, depending on the inflammatory environment.

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“…A comparison of the miRNA expression patterns of PBMCs and paired mononuclear cells isolated from the synovial fluid (SFMCs) of 9 oJIA patients vs. PBMCs from 8 HCs was carried out by Rajendiran and colleagues [105]. Enrolled children received NSAID and 2 of them also received MTX before recruitment.…”

Section: Cell-associated Mirnas In Jia 31 Differentially Expressed Mi...mentioning

confidence: 99%

MicroRNAs in Juvenile Idiopathic Arthritis: State of the Art and Future Perspectives

Pelassa

Raggi

Rossi

et al. 2023

Biology

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Juvenile Idiopathic Arthritis (JIA) represents the most common chronic pediatric arthritis in Western countries and a leading cause of disability in children. Despite recent clinical achievements, patient management is still hindered by a lack of diagnostic/prognostic biomarkers and targeted treatment protocols. MicroRNAs (miRNAs) are short non-coding RNAs playing a key role in gene regulation, and their involvement in many pathologies has been widely reported in the literature. In recent decades, miRNA’s contribution to the regulation of the immune system and the pathogenesis of autoimmune diseases has been demonstrated. Furthermore, miRNAs isolated from patients’ biological samples are currently under investigation for their potential as novel biomarkers. This review aims to provide an overview of the state of the art on miRNA investigation in JIA. The literature addressing the expression of miRNAs in different types of biological samples isolated from JIA patients was reviewed, focusing in particular on their potential application as diagnostic/prognostic biomarkers. The role of miRNAs in the regulation of immune responses in affected joints will also be discussed along with their potential utility as markers of patients’ responses to therapeutic approaches. This information will be of value to investigators in the field of pediatric rheumatology, encouraging further research to increase our knowledge of miRNAs’ potential for future clinical applications in JIA.

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miR-23a contributes to T cellular redox metabolism in juvenile idiopathic oligoarthritis

Cited by 6 publications

References 32 publications

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers

NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA

MicroRNAs in Juvenile Idiopathic Arthritis: State of the Art and Future Perspectives

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