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

Cellular & Molecular Immunology
Chao ZhangHong Tang

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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Citations

May 8, 2018·Cellular & Molecular Immunology·Yankai WenXiaoni Kong
Nov 21, 2017·Cellular & Molecular Immunology·Arvin Iracheta-Vellve, Gyongyi Szabo
Oct 24, 2019·Archives of Toxicology·Hartmut JaeschkeWen-Xing Ding
May 1, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Stephanie J MelchorSarah E Ewald
May 30, 2020·Cellular & Molecular Immunology·Xinwen LinHong Tang
Sep 15, 2018·International Journal of Molecular Sciences·Katrin NeumannGisa Tiegs
Nov 9, 2017·Contrast Media & Molecular Imaging·Bérenger LargeauNicolas Arlicot
May 22, 2019·Scientific Reports·Maria Nogueira de MenezesMaria Regina D'Império-Lima
Jun 19, 2019·Cell Death & Disease·Chenxuan YangMelanie J Scott
Dec 19, 2018·Current Pharmacology Reports·Benjamin L Woolbright, Hartmut Jaeschke
Oct 13, 2020·Frontiers in Immunology·Lu Li, Zhutian Zeng
Nov 19, 2020·Cellular & Molecular Immunology·Yong HeBin Gao
Dec 24, 2020·International Journal of Molecular Sciences·Layla ShojaieLily Dara
May 1, 2021·International Journal of Molecular Sciences·Alessio GerussiPietro Invernizzi
Mar 1, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Hongli GuoJing Xu
Nov 25, 2019··超 张婕华 靳

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Methods Mentioned

BETA
FACS
flow cytometry

Software Mentioned

ImageJ
FlowJo
QWin V3
GraphPad Prism

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