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Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice
Published on: March 10, 2017
Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity
Chao Zhang1, Jin Feng1, Jun Du2
1The Key Laboratory of Infection and Immunity, The Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
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.
Insights
Acetaminophen overdose causes liver injury through IL-1α, not IL-1β. Kupffer cells activate IL-1α, recruiting immune cells to worsen liver damage, suggesting IL-1α as a therapeutic target for acetaminophen-induced liver injury.
Area of Science:
- Immunology
- Hepatology
- Toxicology
Background:
- Acetaminophen (APAP) overdose causes severe liver damage via immune cell activation.
- The role of Interleukin-1 receptor (IL-1R) signaling in APAP-induced liver injury (AILI) is not fully understood.
- Existing research debates the specific IL-1 family members involved in AILI pathogenesis.
Purpose of the Study:
- To elucidate the precise role of IL-1α and IL-1β in AILI.
- To identify the cellular sources and activation mechanisms of key inflammatory mediators in AILI.
- To explore potential therapeutic targets for AILI.
Main Methods:
- Investigated the necessity of NLRP3 inflammasome and IL-1β in AILI.
- Assessed the contribution of IL-1α to APAP-induced hepatotoxicity.
- Utilized mouse models to study Kupffer cell activation via TLR4/MyD88 signaling.
- Analyzed the recruitment and activation of myeloid cells, including neutrophils and monocytes.
Main Results:
- NLRP3 inflammasome and IL-1β are dispensable for AILI.
- IL-1α, not IL-1β, is crucial for liver injury following lethal APAP doses.
- Kupffer cells are the primary source of IL-1α, activated by damaged hepatocytes through TLR4/MyD88.
- IL-1α attracts and activates CD11b+Gr-1+ myeloid cells, exacerbating liver inflammation.
Conclusions:
- MyD88-dependent IL-1α activation in Kupffer cells is central to AILI immunopathogenesis.
- IL-1α plays a significant role in recruiting inflammatory cells to the injured liver.
- Targeting IL-1α presents a promising therapeutic strategy for treating AILI.
