Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation

Wientjens C, Doverman M, Zurkovic J, More T, Surendar J, Nesic S, Sarici C, Utecht TD, Pohl J, Pollock J, Vöhringer D, Hiller K, Thiele C, Wilhelm C (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Immunity Elsevier

DOI: 10.1016/j.immuni.2025.11.018

Abstract

Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to ferroptosis by counteracting lipid peroxidation and reactive oxygen species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.

Authors with CRIS profile

Jonathan Pollock Department of Infection Biology David Vöhringer Department of Infection Biology

Involved external institutions

Universitätsklinikum Bonn DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Technische Universität Braunschweig DE Germany (DE)

How to cite

APA:

Wientjens, C., Doverman, M., Zurkovic, J., More, T., Surendar, J., Nesic, S.,... Wilhelm, C. (2025). Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation. Immunity. https://doi.org/10.1016/j.immuni.2025.11.018

MLA:

Wientjens, Chantal, et al. "Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation." Immunity (2025).

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