Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury

Hao Zhang; Dan Wu; Yanghanzhao Wang; Yuxin Shi; Yuwen Shao; Fu Zeng; Charles B Spencer; Lilibeth Ortoga; Dehua Wu; Changhong Miao

doi:10.1186/s12964-023-01440-6

Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury

Cell Commun Signal. 2024 Feb 2;22(1):97. doi: 10.1186/s12964-023-01440-6.

Authors

Hao Zhang^#^{1

2

3}, Dan Wu^#^{4

5

6}, Yanghanzhao Wang^{4

5

6}, Yuxin Shi^{4

5

6}, Yuwen Shao^{4

5

6}, Fu Zeng^{4

5

6}, Charles B Spencer⁷, Lilibeth Ortoga⁸, Dehua Wu⁹, Changhong Miao^{10

11

12}

Affiliations

¹ Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China. zhang.hao@zs-hospital.sh.cn.
² Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. zhang.hao@zs-hospital.sh.cn.
³ Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China. zhang.hao@zs-hospital.sh.cn.
⁴ Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China.
⁵ Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
⁶ Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China.
⁷ Department of Cardiac surgery, The Ohio State University, Columbus, USA.
⁸ Department of Biomedical Engineering, The Ohio State University, Columbus, USA.
⁹ Department of Anesthesiology, Shanghai Songjiang District Central Hospital, Shanghai, China. wudehua74@163.com.
¹⁰ Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China. miaochanghong_zs@163.com.
¹¹ Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. miaochanghong_zs@163.com.
¹² Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China. miaochanghong_zs@163.com.

^# Contributed equally.

Abstract

Background: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear.

Methods: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4^-/-, Elane^-/- and Cybb^-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways.

Results: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury.

Conclusions: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.

Keywords: Ferritin; Macrophage scavenger receptor; Neutrophil extracellular traps; sepsis-associated acute lung injury.

Publication types

Video-Audio Media
Research Support, Non-U.S. Gov't

MeSH terms

Acute Lung Injury* / metabolism
Animals
Cytokine Release Syndrome
Extracellular Traps* / metabolism
Humans
Inflammation / metabolism
Mice
Neutrophils / metabolism
Reactive Oxygen Species / metabolism
Receptors, Scavenger / metabolism
Sepsis* / complications
Sepsis* / metabolism

Substances

Reactive Oxygen Species
Receptors, Scavenger