The critical role of group 2 innate lymphoid cells (ILC2s) in host defense and mucosal inflammation has been well established, yet the mechanisms underlying ILC2 survival and death remain unknown. Here, we report that ILC2s are vulnerable to ferroptosis, as evidenced by an abundance of ferroptosis signature genes and the accumulation of lipid peroxidation in ILC2s. Ablation of glutathione peroxidase 4 (GPX4) in ILC2s ( Il5 Cre/+ Gpx4 f/f mice) resulted in ferroptosis of ILC2s and diminished their responses. The increase in IFN-γ signaling-enhanced oxidative stress represents the mechanism underlying GPX4 ablation-induced ILC2 ferroptosis. Importantly, Il5 Cre/+ Gpx4 f/f mice exhibited increased susceptibility to DSS-induced colitis. Clinically, ILC2s from inflammatory bowel disease (IBD) patients exhibit reduced GPX4 expression and increased lipid peroxidation. These observations revealed a previously unrecognized role of ferroptosis in ILC2 homeostasis, providing a promising therapeutic opportunity for mucosal inflammatory disorders.
Liu et al. (Mon,) studied this question.