Glutathione peroxidase 4–regulated neutrophil ferroptosis induces systemic autoimmunity

• Published in: Nature immunology Vol. 22; no. 9; pp. 1107 - 1117
• Main Authors: Li, Pengchong, Jiang, Mengdi, Li, Ketian, Li, Hao, Zhou, Yangzhong, Xiao, Xinyue, Xu, Yue, Krishfield, Suzanne, Lipsky, Peter E., Tsokos, George C., Zhang, Xuan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2021; Nature Publishing Group
• Subjects: 631/250/1932; 631/250/38; 692/420/2780/262; 692/699/249/1313/1613; Animals; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; Biomedical and Life Sciences; Biomedicine; Cell death; Cyclic AMP Response Element Modulator - metabolism; Development and progression; Ferroptosis; Ferroptosis - physiology; Genetic aspects; Glutathione; Glutathione peroxidase; Haploinsufficiency; Health aspects; Humans; Immunology; Infectious Diseases; Interferon-alpha - immunology; Leukocytes (neutrophilic); Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Mice; Neutropenia; Neutropenia - pathology; Neutrophils; Neutrophils - immunology; Oxidoreductases; Pathogenesis; Patients; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Physiological aspects; Promoter Regions, Genetic - genetics; Proteinuria; Reactive oxygen species; Reactive Oxygen Species - metabolism; Skin diseases; Skin lesions; Systemic lupus erythematosus; Transcription; α-Interferon; China
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-021-00993-3

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. Zhang and colleagues identify a role for cell death by glutathione peroxidase 4 (GPX4)-regulated ferroptosis in neutrophils from patients with systemic lupus erythematosus, which is triggered by type I interferons and autoreactive antibodies and contributes to lupus pathogenesis. Inhibiting accumulation of oxidative mediators by GPX4 suppresses ferroptosis.