Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis

Jinchao Jia, Mengyan Wang, Jianfen Meng, Yuning Ma, Yang Wang, Naijun Miao, Jialin Teng, Dehao Zhu, Hui Shi, Yue Sun, Honglei Liu, Xiaobing Cheng, Yutong Su, Junna Ye, Huihui Chi, Tingting Liu, Zhuochao Zhou, Liyan Wan, Xia Chen, Fan Wang, Hao Zhang, Jingjing Ben (), Jing Wang (), Chengde Yang () and Qiongyi Hu ()
Additional contact information
Jinchao Jia: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Mengyan Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Jianfen Meng: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yuning Ma: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yang Wang: Shanghai Jiao Tong University School of Medicine
Naijun Miao: Shanghai Jiao Tong University School of Medicine
Jialin Teng: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Dehao Zhu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Hui Shi: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yue Sun: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Honglei Liu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Xiaobing Cheng: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yutong Su: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Junna Ye: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Huihui Chi: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Tingting Liu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Zhuochao Zhou: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Liyan Wan: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Xia Chen: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Fan Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Hao Zhang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Jingjing Ben: Nanjing Medical University
Jing Wang: Shanghai Jiao Tong University School of Medicine
Chengde Yang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Qiongyi Hu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Hyperferritinemic syndrome, an overwhelming inflammatory condition, is characterized by high ferritin levels, systemic inflammation and multi-organ dysfunction, but the pathogenic role of ferritin remains largely unknown. Here we show in an animal model that ferritin administration leads to systemic and hepatic inflammation characterized by excessive neutrophil leukocyte infiltration and neutrophil extracellular trap (NET) formation in the liver tissue. Ferritin-induced NET formation depends on the expression of peptidylarginine deiminase 4 and neutrophil elastase and on reactive oxygen species production. Mechanistically, ferritin exposure increases both overall and cell surface expression of Msr1 on neutrophil leukocytes, and also acts as ligand to Msr1 to trigger the NET formation pathway. Depletion of neutrophil leukocytes or ablation of Msr1 protect mice from tissue damage and the hyperinflammatory response, which further confirms the role of Msr1 as ferritin receptor. The relevance of the animal model is underscored by the observation that enhanced NET formation, increased Msr1 expression and signalling on neutrophil leukocytes are also characteristic to adult-onset Still’s disease (AOSD), a typical hyperferritinemic syndrome. Collectively, our findings demonstrate an essential role of ferritin in NET-mediated cytokine storm, and suggest that targeting NETs or Msr1 may benefit AOSD patients.

Date: 2022
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DOI: 10.1038/s41467-022-34560-7

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