Cited by 99Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyImmunotoxicology and immune responses

Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity

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Zhang, Chao, Feng, Jin, Du, Jun, Zhuo, Zhiyong, Yang, Shuo, Zhang, Weihong, Wang, Weihong, Zhang, Shengyuan +5 more·2018·Cellular & Molecular Immunology

Abstract

The metabolic intermediate of acetaminophen (APAP) can cause severe hepatocyte necrosis, which triggers aberrant immune activation of liver non-parenchymal cells (NPC). Overzealous hepatic inflammation determines the morbidity and mortality of APAP-induced liver injury (AILI). Interleukin-1 receptor (IL-1R) signaling has been shown to play a critical role in various inflammatory conditions, but its precise role and underlying mechanism in AILI remain debatable. Herein, we show that NLRP3 inflammasome activation of IL-1β is dispensable to AILI, whereas IL-1α, the other ligand of IL-1R1, accounts for hepatic injury by a lethal dose of APAP. Furthermore, Kupffer cells function as a major source of activated IL-1α in the liver, which is activated by damaged hepatocytes through TLR4/MyD88 signaling. Finally, IL-1α is able to chemoattract and activate CD11b+Gr-1+ myeloid cells, mostly neutrophils and inflammatory monocytes, to amplify deteriorated inflammation in the lesion. Therefore, this work identifies that MyD88-dependent activation of IL-1α in Kupffer cells plays a central role in the immunopathogenesis of AILI and implicates that IL-1α is a promising therapeutic target for AILI treatment.

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Crossref · 10.1038/cmi.2017.22

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Authors
Zhang, C., Feng, J., Du, J., Zhuo, Z., Yang, S., Zhang, W., Wang, W., Zhang, S., Iwakura, Y., Meng, G., Fu, Y.-X., Hou, B., & Tang, H.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Shanxi University (CN)
  • Tokyo University of Science (JP)
Corresponding author
Tang, Hong
Venue
Cellular & Molecular Immunology
Published
2017-05-15
Volume
15
Issue
11
Pages
973-982
ISSN
  • 1672-7681 (ISSN-L)
  • 2042-0226
OpenAlex
W2616675556
Cited by
99
References
68
Citations by year
2026: 3 · 2025: 10 · 2024: 10 · 2023: 15 · 2022: 12 · 2021: 10 · 2020: 15 · 2019: 13 · 2018: 7 · 2017: 4
FWCI
11.34
Type
journal article
Language
en
Open access
Locations
  • Cellular and Molecular Immunology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (15H05787)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
acetaminophen hepatotoxicity, IL-1α, sterile inflammation, Kupffer cells, NLRP3 inflammasome, IL-1β, TLR4/MyD88 signaling, neutrophils, inflammatory monocytes, myeloid cells, liver necrosis, therapeutic target
MeSH terms
Acetaminophen, Animals, Disease Models, Animal, Inflammation, Kupffer Cells, Signal Transduction, Mice, Knockout, Mice, Receptors, Interleukin-1 Type I, Interleukin-1alpha, Myeloid Differentiation Factor 88, Chemical and Drug Induced Liver Injury

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