gms | German Medical Science

Introduction: Ferroptosis has recently been identified as a novel type of regulated cell death that is driven by lipid peroxidation. Cells have evolved various defense mechanisms to detoxify these toxic lipid peroxides. Especially T cells established a fine-tuned redox-balance as reactive oxygen species are required to activate T cells, while too high amounts are deleterious for their function. We hypothesized that T cells in inflamed tissue have significantly increased needs in antioxidant defense and therefore are much more dependent on mechanism to counteract ferroptosis. The central role of inflammatory T cells in Juvenile idiopathic arthritis (JIA) is undoubtable. We therefore analyzed this mechanism in CD4+ T cells from peripheral blood and from inflamed joints of these patients.

Methods: Ferroptosis and ferroptosis-relevant proteins were analyzed in peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) by flow cytometry. In vitro T cell stimulation assays were performed for metabolic and functional studies.

Results: We could prove that Ferroptosis in CD4+ T cells is regulated by the canonical SLC7A11/Cysteine/Glutathione pathway. Sulfasalazine (SAS), which is currently used for treatment of inflammatory bowel disease and enthesitis-associated arthritis, is a SCL7A11 and Cysteine uptake inhibitor. Despite of its long-lasting therapeutic use, the immune-modulating effects are not clear. Interestingly, inhibition of SLC7A11 by SAS not only induced ferroptosis in CD4+ T cells but also dampened their proinflammatory function (IFN-g and IL-17 production), while regulatory T cell expression was enhanced. Moreover, JIA CD4+ T cells reveal a higher SLC7A11 expression and higher cystine uptake compared to peripheral blood T cells. Our data thereby suggest that JIA T cells dispose mechanism to keep ferroptosis in check, which uncovers a new Achilles heel to treat exaggerated CD4+ T cell responses in JIA.