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

Abstract

Objective Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of unknown origin. The regulation of inflammatory processes involves multiple cellular steps including mRNA transcription and translation. Different miRNAs tightly control these processes. We aimed to determine the roles of specific miRNAs within JIA pathogenesis. Methods We performed a global miRNA expression analysis in parallel in cells from the arthritic joint and peripheral blood of oligoarticular JIA patients and healthy controls. QRT-PCR analysis was used to verify expression of miRNA in T cells. Ex vivo experiments and flow cytometric analyses were used to analyze proliferation and redox metabolism. Results Global miRNA expression analysis demonstrated a different composition of miRNA expression at the site of inflammation compared with peripheral blood. Bioinformatic analysis of predicted miRNA target genes suggest a huge overrepresentation of genes involved in metabolic and oxidative stress pathways in the inflamed joint. Despite enhanced ROS levels within the local inflammatory milieu, JIA T cells are hyperproliferative and reveal an overexpression of miR-23a, which is an inhibitor of PPIF, the regulator of mitochondrial ROS escape. Mitochondrial ROS escape is diminished in JIA T cells resulting in their prolonged survival. Conclusion Our data suggest that miRNA dependent mitochondrial ROS shuttling might be a mechanism that contributes to T cell regulation in JIA at the site of inflammation.

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

“…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.…”

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

“…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 ].…”

“…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 ].…”

“…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).…”

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

“…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.…”