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

• Published in: Antioxidants 2022-12, Vol.11 (12), p.2426
• Main Authors: Rajendiran, Anandhi, Subramanyam, Sudheendra Hebbar, Klemm, Patricia, Jankowski, Vera, van Loosdregt, Jorg, Vastert, Bas, Vollbach, Kristina, Wagner, Norbert, Tenbrock, Klaus, Ohl, Kim
• Format: Article
• Language: English
• Subjects: Antibodies; CD4 antigen; Cell activation; Children; Cloning; DNA methylation; Fatty acids; Flow cytometry; Glucose; Graft versus host disease; Health aspects; Hypoxia; immunometabolism; Inflammation; JIA; Joint diseases; Lymphocytes; Lymphocytes T; Metabolism; Metabolites; Mitochondria; NRF2; NRF2 protein; Oxidative stress; Phenotypes; Physiological aspects; redox metabolism; Rheumatoid arthritis in children; ROS; siRNA; Synovial fluid; T cells; Transcription factors; Transfection; γ-Interferon
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox11122426

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. 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). 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 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. 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.