Cho, Yeonhee; Bukong, Terence Ndonyi 
ORCID: https://orcid.org/0000-0003-3898-0617; Tornai, David et Szabo, Gyongyi
(2021).
Neutrophil extracellular traps formation induced by alcohol generates a unique neutrophil subset with defective neutrophil functions causing liver damage in alcoholic hepatitis
In: EASL 2021: Beating Liver Disease Together, 23 June 2021 - 26 June 2021, virtuel.
Résumé
Background and aims: In alcoholic hepatitis (AH), neutrophil count correlates with poor clinical outcomes. However, it is yet to be explored why neutrophil count increases and whether increased neutrophils induce inflammation and liver damage in AH. Here, we aimed to explore whether neutrophils contribute to alcohol-induced liver damage through increased neutrophil extracellular traps (NET) formation. We identified a unique neutrophil subset (low-density neutrophils, LDNs) and studied mechanisms and consequences of LDNs increase in AH. Method: NETs were assessed by NET assays, co-immunofluorescence staining and microscopic analysis with liver specimen from AH patients and mice. LDNs and high-density neutrophils (HDNs) were isolated from AH patients and controls for RNA sequencing. The NIAAA AH model or 4-week chronic alcohol feeding was utilized for in vivo studies in mice. Results: NET components, including citrullinated histone H3, were significantly elevated in the serum from AH patients, and NET formation was detected in the liver from AH patients and mouse models. Neutrophil depletion in vivo with anti-Ly6G antibody prevented NET formation and reduced alcohol-induced liver damage in mice, supporting the role of NET-mediated liver damage in AH. In patients with AH, we identified low-density neutrophils (LDNs), a unique neutrophil subset, during density separation of blood mononuclear cells. LDNs were present only in AH patients and ot in healthy subjects or NASH patients. AH-specific LDNs expressed markers of mature neutrophils with exhaustive phenotypes based on flow cytometry and transcriptomic profile. We discovered that LDNs are generated from HDNs after alcohol-induced NET formation. Moreover, transcriptomic analysis identified significant reduction of the neutrophil homing receptor, CXCR4, expression and increased transpondin-1 (don’t eat me signal) in AH HDNs and to a greater extent in LDNs compared healthy subjects suggesting that LDNs are defective in homing back to the bone marrow or clearance by phagocytes such as macrophages. Conclusion: Alcohol-induced NET formation contributes to pro- longed liver damage and generates a novel LDN neutrophil subset that has defects in functions and clearance from circulation and/or liver.
| Type de document: | Document issu d'une conférence ou d'un atelier |
|---|---|
| Informations complémentaires: | Journal of Hepatology 75(suppl 2):S205-S206 Parallel sessions: Alcoholic liver disease OS-1393 |
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 22 juin 2022 19:22 |
| Dernière modification: | 22 juin 2022 19:22 |
| URI: | https://espace.inrs.ca/id/eprint/12312 |
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