The spectrum of hyperferritinaemic syndrome encompasses clinical conditions including adult-onset Still disease (AOSD), macrophage activation syndrome, catastrophic anti-phospholipid syndrome and septic shock, as well as severe COVID-19. Emerging evidence suggests that ferritin, rather than being a biomarker of the inflammatory response, might contribute directly to the pathogenic mechanism that results in systemic inflammation. A study now shows that ferritin promotes neutrophil activation and the formation of neutrophil extracellular traps (NETs) via the ferritin receptor macrophage scavenger receptor 1 (MSR1), and highlights the therapeutic potential of targeting this pathway.
“Hyperferritinaemia and neutrophil activation are hallmarks of AOSD,” notes corresponding author Qiongyi Hu. “This study reveals the pro-inflammatory role of ferritin, thereby improving the understanding of the common mechanisms behind the spectrum of hyperferritinaemic syndrome.”
In the study, mice treated with intraperitoneally administered ferritin developed systemic inflammation, characterized by a cytokine storm, as well as hepatic inflammation, with increased recruitment of neutrophils and markers of NET formation evident in liver tissue. Further investigations established that neutrophils are essential for ferritin-induced inflammation, and that peptidylarginine deiminase 4, neutrophil elastase and reactive oxygen species are indispensable for NET formation.
Exposure to ferritin increased the expression of MSR1 on mouse and human neutrophils. Ferritin-induced NET formation was reduced in human neutrophils treated with the MSR1 antagonist fucoidan and in Msr1−/− mice, which also displayed attenuated liver inflammation and injury compared with wild-type mice.
Notably, hyperferritinaemia was also shown to contribute to NET formation in neutrophils from patients with AOSD, and treatment with an MSR1 inhibitor abrogated ferritin-induced NET formation in these cells.
The researchers plan to further explore the mechanisms by which ferritin-induced NETs can promote a cytokine storm in patients with AOSD, as well as the potential of targeting the ferritin–MSR1–NET pathway in AOSD and other forms of hyperferritinaemic syndrome.
Jia, J. et al. Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis. Nat. Commun. 13, 6804 (2022)
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Onuora, S. Ferritin-induced NETs lead to cytokine storm in AOSD. Nat Rev Rheumatol 19, 61 (2023). https://doi.org/10.1038/s41584-022-00899-w