Figure 1. Model for dual role of 15LO1 in asthma related to type 2 inflammation.
IL-4 and IL-13 induce IL-4Rα–dependent signaling to drive ALOX15 (15LO1) expression in human airway epithelial cells (HAECs). 15LO1 can add molecular oxygen to free AA, forming HpETE that is rapidly reduced to 15(S)-HETE, which in turn can be converted into 5-oxo-15(S)-HETE, eoxin C4, and other detectable mediators found in biological fluids. 15LO1 also associates with PEBP in the cell membrane, activating ERK (leading to potentiated expression of additional type 2 inflammatory proteins) and switching the 15LO1 substrate preference to PE-esterified AA. The resultant HpETE-PE triggers ferroptosis unless it is reduced by GPX. This reduction requires GSH, which is maintained by the glutamic acid transporter protein SLC7A11. IL-13 increases both GPX and SLC7A11 expression, suggesting that a coordinated system maintains cellular redox balance. Perturbations in this system, such as diminished GSH availability, may favor ferroptosis over cytoprotection, leading to epithelial damage. Red color indicates proteins that are upregulated in epithelial cells by IL-4 and IL-13.