Int J Biol Sci 2022; 18(8):3337-3357. doi:10.7150/ijbs.69141 This issue Cite

Research Paper

Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells

Hao Zhang, MD, PhD1,3,11*, Jinlong Liu, PhD2*, Yilu Zhou8*, Mengdi Qu, PhD1, Yanghanzhao Wang, MD1, Kefang Guo, MD, PhD1, Ruling Shen, PhD7, Zhirong Sun, MD, PhD4, Juan P. Cata, MD5,6, Shuofei Yang, MD, PhD10✉, Wankun Chen, MD, PhD1,2,9✉, Changhong Miao, MD, PhD1,3,9,11✉

1. Department of Anesthesiology, Zhongshan Hospital, Fudan University; Cancer Center, Zhongshan Hospital, Fudan University.
2. Fudan Zhangjiang Institute, Shanghai 201203, China.
3. Department of Anesthesiology, Shanghai Medical Colleague, Fudan University, 201203, Shanghai, China.
4. Department of Anesthesiology, Shanghai Cancer Center, Shanghai, China.
5. Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Centre, Houston, TX, United States.
6. Anesthesiology and Surgical Oncology Research Group, Houston, TX, United States.
7. Shanghai Laboratory Animal Research Center, 201203, Shanghai, China.
8. Department of Anesthesiology, Shanghai first Maternity and infant Hospital, Tongji University school of medicine, Shanghai, China.
9. Department of Anesthesiology, Jinshan Hospital, Fudan University, Shanghai, China.
10. Department of Vascular Surgery, Renji Hospital,School of Medicine, Shanghai Jiaotong University, Shanghai, China.
11. Shanghai Key Laboratory of Perioperative Stress and Protection.
*These authors contributed equally to this work.

Citation:
Zhang H, Liu J, Zhou Y, Qu M, Wang Y, Guo K, Shen R, Sun Z, Cata JP, Yang S, Chen W, Miao C. Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int J Biol Sci 2022; 18(8):3337-3357. doi:10.7150/ijbs.69141. https://www.ijbs.com/v18p3337.htm
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Abstract

Graphic abstract

Neutrophil extracellular traps (NETs) production is a major strategy employed by polymorphonuclear neutrophils (PMNs) to fight against microbes. NETs have been implicated in the pathogenesis of various lung injuries, although few studies have explored NETs in sepsis-associated acute lung injury (SI-ALI). Here, we demonstrate a major contribution of NETs to the pathology of sepsis-associated ALI by inducing ferroptosis of alveolar epithelial cells. Using both in vitro and in vivo studies, our findings show enhanced NETs accumulation in sepsis-associated ALI patients and mice, as well as the closely related upregulation of ferroptosis, the induction of which depends on METTL3-induced m6A modification of GPX4. Using a CLP-induced sepsis-associated ALI mouse model established with METTL3-/- versus WT mice, in addition to METTL3 knockout and overexpression in vitro, we elucidated and confirmed the critical role of ferroptosis in NETs-induced ALI. These findings support a role for NETs-induced METTL3 modification and the subsequent induction of ferroptosis in the pathogenesis of sepsis-associated ALI.

Keywords: Neutrophil extracellular traps, sepsis-associated acute lung injury, N6-Methylation, ferroptosis


Citation styles

APA
Zhang, H., Liu, J., Zhou, Y., Qu, M., Wang, Y., Guo, K., Shen, R., Sun, Z., Cata, J.P., Yang, S., Chen, W., Miao, C. (2022). Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. International Journal of Biological Sciences, 18(8), 3337-3357. https://doi.org/10.7150/ijbs.69141.

ACS
Zhang, H.; Liu, J.; Zhou, Y.; Qu, M.; Wang, Y.; Guo, K.; Shen, R.; Sun, Z.; Cata, J.P.; Yang, S.; Chen, W.; Miao, C. Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int. J. Biol. Sci. 2022, 18 (8), 3337-3357. DOI: 10.7150/ijbs.69141.

NLM
Zhang H, Liu J, Zhou Y, Qu M, Wang Y, Guo K, Shen R, Sun Z, Cata JP, Yang S, Chen W, Miao C. Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int J Biol Sci 2022; 18(8):3337-3357. doi:10.7150/ijbs.69141. https://www.ijbs.com/v18p3337.htm

CSE
Zhang H, Liu J, Zhou Y, Qu M, Wang Y, Guo K, Shen R, Sun Z, Cata JP, Yang S, Chen W, Miao C. 2022. Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int J Biol Sci. 18(8):3337-3357.

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