The Role of Ferroptosis in Type 2 Immunity

Abstract

Tissue-resident immune cells are crucial for the maintenance and protection of barrier tissues, while aberrant activation can lead to pathologies including allergic airway inflammation. Type 2 innate lymphoid cells (ILC2) in allergen-driven chronic airway inflammation alter metabolic activity characterized by increased lipid metabolism and the acquisition of external fatty acids. Active metabolism and high amounts of lipids might potentially render pathogenic ILC2 susceptible to reactive oxygen species (ROS) and ferroptosis. Here we found, that pathogenic ILC2 in the context of allergic airway inflammation exhibited a high metabolic flexibility, converging on the availability of the amino acid cysteine. Cystine uptake fueled glutathione (GSH) synthesis supported a higher redox balancing capacity. The coordinated up regulation of the antioxidant systems glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) promoted the detoxification of cellular ROS and Lipid peroxides. This enhanced redox capacity conferred ferroptosis resistance and supported accelerated lipid metabolism, and thereby promoted the expansion of pathogenic ILC2 and Th2 cells during allergic airway inflammation. Consequently, genetic ablation of <em>Gpx4</em> or <em>Txnrd1</em> in ILC2, as well as pharmacological inhibition of TXNRD1 with intranasal TRi-1 application, impaired lipid metabolism, limited ILC2 and Th2 accumulation, and markedly reduced airway inflammation. These findings revealed that the increased dependence of pathogenic type 2 immune cells on antioxidant systems constitutes a metabolic vulnerability that can be therapeutically targeted to restrain type 2 inflammation in asthma.