P15 Polyunsaturated fatty acids enhance cell death in Jurkat T cells: implications for dysregulated cell death pathways in skin disease

Introduction and aims Psoriasis is an inflammatory skin condition with increased inflammatory cell death (ferroptosis and pyroptosis) and reduced noninflammatory cell death (apoptosis). Resident and infiltrating cutaneous T cells metabolize fatty acids (FAs) into inflammatory or anti-inflammatory lipid mediators; their production is altered in psoriasis skin. We aim to explore how these lipids may influence different cell death pathways. Methods Naïve and anti-CD3/CD28-activated Jurkat T cells were treated with arachidonic acid (AA), linoleic acid (LA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) or palmitic acid (PA) (0–100 µmol L–1; 24 h) and viability assessed by CCK8. To explore whether FAs enhance or protect against cell death, naïve Jurkat T cells were treated with AA, LA, PA, DHA or EPA (20 μmol L–1; 24 h) to generate FA-loaded cells and divided into two groups. Group one were activated (anti-CD3/CD28) and then exposed to cell death inducers (dox, 0.15 μmol L–1; erastin, 5 μmol L–1; nigericin, 1.5 μmol L–1). Group two remained naïve and treated with FAs only (24 h), before exposure to cell death inducers (24 h). Cells were then stained with anti-CD69 and Zombie near-infrared (NIR) (activated) or Zombie NIR (naïve), before fixing and assessing using flow cytometry. Results Polyunsaturated FAs (AA, LA, DHA and EPA) reduced viability (< 80%) in activated and naïve Jurkat T cells. PA (saturated FA) did not induce cell death in naïve or activated T cells, but specifically sensitized cells to erastin-induced ferroptosis. AA, LA, DHA and EPA all enhanced dox-induced apoptosis, erastin-induced ferroptosis and nigericin-induced pyroptosis. Conclusions Polyunsaturated FAs enhanced inflammatory (ferroptosis and pyroptosis) and noninflammatory (apoptosis) cell death, while the saturated FA, PA, enhanced only erastin-induced ferroptosis. PA cannot be metabolized to lipid mediators through the same pathways as polyunsaturated FAs suggesting it could initiate cell death through alternative mechanisms. Pretreating T cells with FAs may sensitize them to pharmacological treatments enhancing their efficacy and improving therapeutic potential.