Ficolin-A/2 Aggravated Severe Lung Injury through Neutrophil Extracellular Traps Mediated by Gasdermin D-Induced Pyroptosis

Li Huang; Xiaowu Tan; Weixia Xuan; Qing Luo; Li Xie; Yunzhu Xi; Rong Li; Li Li; Feifan Li; Meiyun Zhao; Yongliang Jiang; Xu Wu

doi:10.1016/j.ajpath.2024.02.011

Ficolin-A/2 Aggravated Severe Lung Injury through Neutrophil Extracellular Traps Mediated by Gasdermin D-Induced Pyroptosis

Am J Pathol. 2024 Mar 3:S0002-9440(24)00082-8. doi: 10.1016/j.ajpath.2024.02.011. Online ahead of print.

Authors

Li Huang¹, Xiaowu Tan², Weixia Xuan³, Qing Luo², Li Xie², Yunzhu Xi², Rong Li², Li Li², Feifan Li², Meiyun Zhao², Yongliang Jiang⁴, Xu Wu⁵

Affiliations

¹ Department of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Henan, China; Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Henan, China.
² Pulmonary and Critical Care Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Henan, China.
³ Department of Respiratory and Critical Care Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
⁴ Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Henan, China. Electronic address: yvfei316@163.com.
⁵ Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Henan, China; Pulmonary and Critical Care Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Henan, China. Electronic address: wx1048946906@126.com.

PMID: 38442803
DOI: 10.1016/j.ajpath.2024.02.011

Abstract

Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. This study investigated whether ficolin-A influences NET formation through pyroptosis to exacerbate lipopolysaccharide (LPS)-induced lung injury. The expression of ficolin-A/2, NETs, and pyroptosis-related molecules was investigated in animal and cell models. Knockout and knockdown (recombinant protein) methods were used to elucidate regulatory mechanisms. The Pearson correlation coefficient was used to analyze the correlation between ficolins and pyroptosis- and NET-related markers in clinical samples. In this study, ficolin-2 (similar to ficolin-A) showed significant overexpression in patients with acute respiratory distress syndrome. In vivo, knockout of ficolin-A, but not ficolin-B, attenuated lung inflammation and inhibited NET formation in the LPS-induced mouse model. DNase I further alleviated lung inflammation and NET formation in ficolin-A knockout mice. In vitro, neutrophils derived from Fcna^-/- mice showed less pyroptosis and necroptosis than those from the control group after LPS stimulation. Additionally, gasdermin D knockdown or Nod-like receptor protein 3 inhibitor reduced NET formation. Addition of recombinant ficolin-2 protein to human peripheral blood neutrophils promoted NET formation and pyroptosis after LPS stimulation, whereas ficolin-2 knockdown had the opposite effect. Acute respiratory distress syndrome patients showed increased levels of pyroptosis- and NET-related markers, which were correlated positively with ficolin-2 levels. In conclusion, these results suggested that ficolin-A/2 exacerbated NET formation and LPS-induced lung injury via gasdermin D-mediated pyroptosis.