Ficolin-A/2 Aggravates Severe Lung Injury Through Neutrophil Extracellular Traps Mediated by Gasdermin D-Induced Pyroptosis.
The American journal of pathology(2024)
摘要
Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. This study investigated whether fi colin-A in fl uenced NET formation through pyroptosis to exacerbate lipopolysaccharide (LPS)-induced lung injury. The expression of fi colin-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 fi colins and pyroptosis- and NET -related markers in clinical samples. In this study, fi colin-2 (similar to fi colin-A) showed signi fi cant overexpression in patients with acute respiratory distress syndrome. In vivo , knockout of Fcna , but not Fcnb , attenuated lung in fl ammation and inhibited NET formation in the LPS-induced mouse model. DNase I further alleviated lung in fl ammation and NET formation in Fcna knockout mice. In vitro , neutrophils derived from Fcna (- / -) mice showed less pyroptosis and necroptosis than those from the control group after LPS stimulation. Additionally, GSDMD knockdown or Nod -like receptor protein 3 inhibitor reduced NET formation. Addition of recombinant fi colin-2 protein to human peripheral blood neutrophils promoted NET formation and pyroptosis after LPS stimulation, whereas Fcn2 knockdown had the opposite effect. Acute respiratory distress syndrome patients showed increased levels of pyroptosis- and NET -related markers, which were correlated positively with fi colin-2 levels. In conclusion, these results suggested that fi colin-A/2 exacerbated NET formation and LPSinduced lung injury via gasdermin D -mediated pyroptosis. (Am J Pathol 2024, 194: 989 - 1006; https://doi.org/10.1016/j.ajpath.2024.02.011)
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关键词
ARDS,Ficolin-A/2,pyroptosis,GSDMD,NLRP3,NET,Lung injury
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