The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.

中性粒细胞死亡与自身免疫发展之间的联系尚未得到彻底探索。在这里，我们表明来自狼疮易发小鼠或系统性红斑狼疮 (SLE) 患者的中性粒细胞会发生铁死亡。从机制上讲，血清中存在的自身抗体和干扰素-α通过增强转录抑制因子 CREMα 与谷胱甘肽过氧化物酶 4（Gpx4，铁死亡的关键调节因子）启动子的结合，诱导中性粒细胞铁死亡，从而导致Gpx4的表达受抑制，随后脂质-活性氧。此外，发现具有中性粒细胞特异性Gpx4的小鼠单倍体不足概括了人类 SLE 的关键临床特征，包括自身抗体、中性粒细胞减少、皮肤损伤和蛋白尿，并且用特定的铁死亡抑制剂治疗显着改善了狼疮易感小鼠的疾病严重程度，揭示了中性粒细胞铁死亡在狼疮发病机制中的作用。总之，我们的数据表明中性粒细胞铁死亡是 SLE 中性粒细胞减少的重要驱动因素，并且在很大程度上促成了疾病表现。