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Neutrophils Die Hard: Unique Survival of Neutrophils in Alcoholic Hepatitis after Extracellular Traps (NETs) Formation

Cho, Yeonhee, Bukong, Terence Ndonyi, Tornai, David, Catalano, Donna et Szabo, Gyongyi . Neutrophils Die Hard: Unique Survival of Neutrophils in Alcoholic Hepatitis after Extracellular Traps (NETs) Formation In: AASLD: The liver Meeting, 13-16 November 2020, virtuel.

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Résumé

Background: Neutrophils are bone marrow derived leukocytes that play a critical role in host defense. Significant increase in neutrophil counts in peripheral blood and the liver is consistently reported in alcoholic hepatitis (AH) patients. However, little is known about how neutrophils are involved in development and/or progression of AH. The aim of this study was to examine if neutrophils contribute to AH pathogenesis through uncontrolled neutrophil extracellular traps (NETs) formation and to identify the fate of neutrophils after alcohol-induced NETs release.

Methods: Mice received Lieber-DeCarlie diet containing 5% ethanol or calorie matched liquid diet for 4 weeks. Anti-Ly6G (1A8) or isotype antibody was injected for in vivo neutrophil depletion. We performed immunofluorescence (IF) staining to detect in vivo NETs formation in livers from AH patients and mouse model. Human peripheral neutrophils were monitored with confocal live imaging system to observe cellular fate after NETs release. Reactive oxygen species (ROS) formation and phagocytosis in alcohol-exposed neutrophils were measured through flow cytometry.

Results: Neutrophil infiltration and NETs formation was increased in the liver from AH patients and in the mouse model compared to controls. In vivo neutrophil depletion in mice prevented EtOH-induced NETs formation in the liver and reduced alcohol-induced ALT increase, indicating neutrophil-mediated liver injury in AH. Using flow cytometry and confocal microscopy we found that unlike canonical NETs formation which results in cell death, neutrophils remain live after alcohol induced NETs release with intact plasma membrane. Moreover, we discovered a unique neutrophil population in peripheral blood mononuclear cell populations (PBMCs) fraction in AH patients that is not present in healthy subjects or non-alcoholic steatohepatitis. Our results suggest that neutrophils that survived after NETs release represent this newly identified neutrophil population in AH. The alcohol-exposed neutrophils showed functional defects such as impaired ROS formation and phagocytosis in response to LPS and HMGB1, suggesting a possible explanation for the discrepancy that AH patients are more susceptible to infection despite higher neutrophil counts.

Conclusion: Our study shows that neutrophils contribute to alcohol-induced liver damage through increased NETs formation. In AH neutrophils uniquely remain viable after NETs release, and show functional defects.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche scientifique no 262 Hepatology 72(S1):179A
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 15 juill. 2021 00:36
Dernière modification: 15 juill. 2021 00:36
URI: https://espace.inrs.ca/id/eprint/11793

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