Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Cell Death Dis. 2024 Sep 19;15(9):687. doi: 10.1038/s41419-024-07060-3.
Group 3 innate lymphoid cells (ILC3s) are essential for both pathogen defense and tissue homeostasis in the intestine. Dysfunction of ILC3s could lead to increased susceptibility to intestinal inflammation. However, the precise mechanisms governing the maintenance of intestinal ILC3s are yet to be fully elucidated. Here, we demonstrated that ferroptosis is vital for regulating the survival of intestinal ILC3. Ferroptosis-related genes, including GPX4, a key regulator of ferroptosis, were found to be upregulated in intestinal mucosal ILC3s from ulcerative colitis patients. Deletion of GPX4 resulted in a decrease in NKp46ILC3 cell numbers, impaired production of IL-22 and IL-17A, and exacerbated intestinal inflammation in a T cell-independent manner. Our mechanistic studies revealed that GPX4-mediated ferroptosis in NKp46ILC3 cells was regulated by the LCN2-p38-ATF4-xCT signaling pathway. Mice lacking LCN2 in ILC3s or administration of a p38 pathway inhibitor exhibited similar phenotypes of ILC3 and colitis to those observed in GPX4 conditional knock-out mice. These observations provide novel insights into therapeutic strategies for intestinal inflammation by modulating ILC3 ferroptosis.
3 组固有淋巴细胞 (ILC3) 对于肠道的病原体防御和组织稳态都是必不可少的。ILC3 功能障碍可能导致对肠道炎症的易感性增加。然而，调节肠道 ILC3 的维持的确切机制尚未完全阐明。在这里，我们证明铁死亡对于调节肠道 ILC3 的存活至关重要。铁死亡相关基因，包括铁死亡的关键调节因子 GPX4，在溃疡性结肠炎患者的肠道黏膜 ILC3 中上调。GPX4 的缺失导致 NKp46ILC3 细胞数量减少，IL-22 和 IL-17A 的产生受损，并以 T 细胞非依赖的方式加剧肠道炎症。我们的机制研究表明，GPX4 介导的 NKp46ILC3 细胞铁死亡受 LCN2-p38-ATF4-xCT 信号通路调节。缺乏 ILC3 中的 LCN2 或给予 p38 通路抑制剂的小鼠表现出与 GPX4 条件性敲除小鼠相似的 ILC3 和结肠炎表型。这些观察结果为通过调节 ILC3 铁死亡治疗肠道炎症提供了新的见解。
