Evidence map›Paper›PMID 36063965›Full record

ArticleJournal of hepatology2023

Neutrophil extracellular traps contribute to liver damage and increase defective low-density neutrophils in alcohol-associated hepatitis.

Yeonhee Cho, Terence Ndonyi Bukong, David Tornai, Mrigya Babuta, Ioannis S Vlachos, Eleni Kanata, Donna Catalano, Gyongyi Szabo

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
93citing papers in PubMed, 1 pooled it
9.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

93 citing papers in PubMed, 1 synthesis or guideline pooled it, 123 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. [Alcohol liver disease: immunoregulatory mechanisms and precision therapeutic targets].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2026
    Review
  4. Review
  5. Therapeutics for Alcohol-Associated Liver Disease.Annual review of pharmacology and toxicology · 2026
    Review
  6. Review
  7. Article
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  10. Article
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  12. Galectin-9Aging cell · 2026
    Article
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33 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 5 institutions in 3 countries.

Yeonhee ChoDepartment of Medicine, University of Massachusetts Medical School, Worcester, MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.
Terence Ndonyi BukongArmand-Frappier Sante Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, Quebec, Canada.
David TornaiDivision of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Mrigya BabutaDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.
Ioannis S VlachosHarvard Medical School Initiative for RNA Medicine, Boston, MA, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eleni KanataHarvard Medical School Initiative for RNA Medicine, Boston, MA, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Donna CatalanoDepartment of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Gyongyi SzaboDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: gszabo1@bidmc.harvard.edu.
Broad Institute · USBeth Israel Deaconess Medical Center · USInstitut National de la Recherche Scientifique · CAUniversity of Debrecen · HUUniversity of Massachusetts Chan Medical School · US

Funding

Alcohol and Monocyte Signaling Administrative SupplementR01AA011576 · NIAAA · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Gyongyi Szabo · 1998 to 2026
$9.3M
TLR4 Signaling in alcoholic liver diseaseR01AA017729 · NIAAA · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SZABO, GYONGYI · 2009 to 2021
$4.3M
Alcoholic Hepatitis Clinical and Translational Network Late Phase Clinical Trials and Observational Studies 4/9U01AA026977 · NIAAA · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SZABO, GYONGYI · 2018 to 2022
$1.8M
Biomarkers of Disease in Alcoholic Hepatitis Administrative SupplementU01AA026933 · NIAAA · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SZABO, GYONGYI · 2018 to 2023
$1.4M
NIAAA NIH HHS R01 AA011576NIAAA NIH HHS R01 AA017729NIAAA NIH HHS U01 AA026933NIAAA NIH HHS U01 AA026977
6 · The paper itself

Abstract

BACKGROUND &

aimsIn alcohol-associated hepatitis (AH), inflammation and neutrophil counts correlate with poor clinical outcomes. Here, we investigated how neutrophils contribute to liver damage in AH.

methodsWe isolated blood neutrophils from individuals with AH to examine neutrophil extracellular traps (NETs) and performed RNA sequencing to explore their unique characteristics.

resultsWe observed a significant increase in NET production in AH. We also observed a unique low-density neutrophil (LDN) population in individuals with AH and alcohol-fed mice that was not present in healthy controls. Transcriptome analysis of peripheral LDNs and high-density neutrophils (HDNs) from individuals with AH revealed that LDNs exhibit a functionally exhausted phenotype, while HDNs are activated. Indeed, AH HDNs exhibited increased resting reactive oxygen species (ROS) production and produced more ROS upon lipopolysaccharide stimulation than control HDNs, whereas AH LDNs failed to respond to lipopolysaccharide. We show that LDNs are generated from HDNs after alcohol-induced NET release in vitro, and this LDN subset has decreased functionality, including reduced phagocytic capacity. Moreover, LDNs showed reduced homing capacity and clearance by macrophage efferocytosis; therefore, dysfunctional neutrophils could remain in the circulation and liver. Depletion of both HDNs and LDNs in vivo prevented alcohol-induced NET production and liver damage in mice. Granulocyte-colony stimulating factor treatment also ameliorated alcohol-induced liver injury in mice.

conclusionNeutrophils contribute to liver damage through increased NET formation which increases defective LDNs in AH. Alcohol induces phenotypic changes in neutrophils; HDNs are activated whereas LDNs are defective. Our findings provide mechanistic insights that could guide the development of therapeutic interventions for AH. IMPACT AND IMPLICATIONS: In this study we discovered heterogeneity of neutrophils in alcohol-associated hepatitis, including high-density and low-density neutrophils that show hyper-activated or exhausted transcriptomic profiles, respectively. We found that alcohol induces neutrophil extracellular trap (NET) formation, which contributes to liver damage. NET release by high-density neutrophils resulted in low-density neutrophils that reside in the liver and escape clean-up by macrophages. Our findings help to understand the opposing neutrophil phenotypes observed in individuals with alcohol-associated hepatitis and provide mechanistic insights that could guide therapeutic strategies targeting neutrophils.

Indexed as

Extracellular TrapsHepatitis, AlcoholicAnimalsLipopolysaccharidesMiceNeutrophilsReactive Oxygen SpeciesLipopolysaccharidesReactive Oxygen Speciesalcoholic hepatitisLow-density neutrophils (LDNs)Neutrophil extracellular traps (NETs)

Identifiers

PMID36063965
PMCPMC11910133
OpenAlexW4294584780

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.