In allergic asthma, so-called ILC2 and Th2 cells are central drivers of inflammation. They produce messenger substances that increase mucus formation and immune cell influx. At the same time, the inflamed lung tissue is rich in free fatty acids and oxidative molecules – conditions that normally endanger cells.
The study shows that the pathogenic ILC2 absorb large amounts of these fats and incorporate them into their membranes. In order not to die from so-called ferroptosis, an iron-dependent cell death caused by oxidized lipids, they massively activate their antioxidant systems. The enzymes GPX4 and TXNRD1 in particular play a central role. They defuse harmful lipid peroxides and enable cells to survive and multiply despite the stressful environment.
Research in mouse models
“These immune cells move in an environment that is actually toxic for them. They only survive because they extremely ramp up their own protective programs,” explains first author Chantal Wientjens, who researches in the Wilhelm working group at the Institute of Chemistry and Clinical Pharmacology at the UKB and is a doctoral student at the University of Bonn. “Our data shows that as soon as we specifically disrupt this protection, the cells lose their ability to drive allergic inflammation.”
To test this approach, the Bonn team inhibited the thioredoxin pathway using an agent that blocks the enzyme TXNRD1. In mouse models, this led to significantly fewer ILC2 accumulating in the lungs. As a result, the production of the typical type 2 cytokines IL-5 and IL-13 as well as the number of eosinophils and mucus production decreased. Overall, the allergic reaction was significantly smaller.
Immune function & metabolism
Study leader Christoph Wilhelm, Chair of Immunopathology at the Institute of Clinical Chemistry and Clinical Pharmacology at the UKB and member of the ImmunoSensation² Cluster of Excellence at the University of Bonn, explains: “Pathogenic type 2 immune cells are surprisingly dependent on their antioxidant ‘lifeline’. This opens up a very targeted therapeutic approach: In the future, we could slow down the metabolism of overactive immune cells without weakening the immune system as a whole. That is The perspective is exciting, even if we are still at the beginning of research here.”
The study highlights how closely immune function and metabolism are intertwined. In order to remain active in the fat-rich and oxidative environment of the inflamed lung, pathogenic ILC2 flexibly adapt their metabolism – and in doing so inadvertently create the very dependency that makes them vulnerable.
Source: Bonn University Hospital
Original publication: Chantal Wientjens et al.; Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation; ImmunityDecember 2025, DOI: 10.1016/j.immuni.2025.11.018
