1. Academic Validation
  2. Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity

Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity

  • Nat Immunol. 2021 Sep;22(9):1107-1117. doi: 10.1038/s41590-021-00993-3.
Pengchong Li  # 1 2 Mengdi Jiang  # 1 2 Ketian Li  # 1 2 Hao Li  # 3 Yangzhong Zhou 4 Xinyue Xiao 1 Yue Xu 2 Suzanne Krishfield 3 Peter E Lipsky 5 George C Tsokos 6 Xuan Zhang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Clinical Immunology Centre, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 RILITE Research Institute and AMPEL BioSolutions, Charlottesville, VA, USA. [email protected].
  • 6 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
  • 7 Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China. [email protected].
  • # Contributed equally.
Abstract

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.

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