Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity
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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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In a mouse model of acetaminophen-induced acute liver injury, TLR4/MyD88-dependent release of IL-1α by KCs caused the inflammation that led to liver damage.
“In a mouse model of acetaminophen-induced acute liver injury, others found that TLR4/MyD88-dependent release of IL-1α by KCs caused the inflammation that led to liver damage.64”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [64]
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Self-citation
- 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
- ORCID
- Venue
- Cellular & Molecular Immunology
- Published
- 2017-05-15
- Volume
- 15
- Issue
- 11
- Pages
- 973-982
- ISSN
- 1672-7681 (ISSN-L)
- 2042-0226
- PMC
- PMC6207754
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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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