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

Chao Zhang, Jin Feng, Jun Du, Zhiyong Zhuo, Shuo Yang, Weihong Zhang, Weihong Wang, Shengyuan Zhang, Yoichiro Iwakura, Guangxun Meng, Yang-Xin Fu, Baidong Hou, Hong Tang

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)973-982
Number of pages10
JournalCellular and Molecular Immunology
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2018

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Keywords

  • acetaminophen
  • IL-α
  • Kupffer cells
  • sterile immunity
  • TLR4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

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. (2018). Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cellular and Molecular Immunology, 15(11), 973-982. https://doi.org/10.1038/cmi.2017.22