α-Tocopherol ameliorates allergic airway inflammation by regulating ILC2 ferroptosis in an LKB1-dependent manner

Abstract

Dietary immunization plays a pivotal role in modulating allergic airway inflammation mediated by group 2 innate lymphoid cells (ILC2s). This study identifies α-tocopherol (α-Toc), a component of vitamin E, as a key regulator of allergic airway inflammation. Transcriptomic analysis of lung ILC2s from mice treated with α-Toc reveals reduced expression of scavenger receptor class B type 1 (SCARB1) and inhibition of the liver kinase B1 (LKB1)-AMPK/mTOR signaling pathway. Mice lacking LKB1 or treated with a SCARB1 antagonist demonstrate a significant reduction in ILC2 abundance, impaired ILC2 functionality, and diminished lung inflammation. Importantly, α-Toc fails to alleviate allergic airway inflammation in LKB1-deficient mice. Mechanistically, LKB1 deficiency reduces lung inflammation by promoting ferroptosis in ILC2s. Specifically, LKB1 regulates the expression of the Krüppel-like Factor 4-glutathione peroxidase 4 complex, which is crucial for modulating ILC2 ferroptosis and allergic airway inflammation. ILC2 activation and LKB1-mediated ferroptosis were also observed in patients with asthma. In ex vivo cultures of human blood ILC2s, α-Toc treatment significantly inhibited ILC2 activation and LKB1-mediated ferroptosis. These findings enhance our understanding of dietary immunization and suggest potential therapeutic applications for α-Toc in asthma management.

Keywords: GPX4; LKB1; allergic airway inflammation; asthma; ferroptosis; group 2 innate lymphoid cells; α-tocopherol.