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

Anandhi Rajendiran, Sudheendra Hebbar Subramanyam, Patricia Klemm, Vera Jankowski, Jorg van Loosdregt, Bas Vastert, Kristina Vollbach, Norbert Wagner, Klaus Tenbrock, Kim Ohl

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Abstract

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.

Original languageEnglish
Article number2426
JournalAntioxidants (Basel, Switzerland)
Volume11
Issue number12
DOIs
Publication statusPublished - 8 Dec 2022

Keywords

  • JIA
  • NRF2
  • ROS
  • immunometabolism
  • redox metabolism

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