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

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 CD11bGr-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.

Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives

“…The very limited IL-1β formation as reported in mice 123,124 was also confirmed in APAP overdose patients 111 suggesting that inflammasome activation and IL-1β formation are of limited importance for APAP-induced liver injury in mice and humans. However, Zhang and coworkers 124 suggested a role for IL-1α in the pathophysiology. IL-1α is generated by Kupffer cells through TLR4 stimulation but not by TLR9- or TLR3-dependent mechanisms 124 .…”

“…Interestingly, these authors did also not find a protection in caspase-1 or Nalp3-deficient mice 124 . The very limited IL-1β formation as reported in mice 123,124 was also confirmed in APAP overdose patients 111 suggesting that inflammasome activation and IL-1β formation are of limited importance for APAP-induced liver injury in mice and humans. However, Zhang and coworkers 124 suggested a role for IL-1α in the pathophysiology.…”

“…In addition, caspase inhibitors prevented IL-1β formation but did not protect and adding high doses of exogenous IL-1β enhanced neutrophil recruitment but did not affect the APAP-induced liver injury 123 . More recently another study showed that neither mice deficient in IL-1β nor treatment with an anti-IL-lβ antibody protected against APAP hepatotoxicity 124 . Interestingly, these authors did also not find a protection in caspase-1 or Nalp3-deficient mice 124 .…”

“…More recently another study showed that neither mice deficient in IL-1β nor treatment with an anti-IL-lβ antibody protected against APAP hepatotoxicity 124 . Interestingly, these authors did also not find a protection in caspase-1 or Nalp3-deficient mice 124 . The very limited IL-1β formation as reported in mice 123,124 was also confirmed in APAP overdose patients 111 suggesting that inflammasome activation and IL-1β formation are of limited importance for APAP-induced liver injury in mice and humans.…”

“…However, Zhang and coworkers 124 suggested a role for IL-1α in the pathophysiology. IL-1α is generated by Kupffer cells through TLR4 stimulation but not by TLR9- or TLR3-dependent mechanisms 124 . In their hands, an anti-IL-1α antibody protected and mice deficient in IL-1α or the IL-1 receptor experienced less injury after an APAP overdose 124 .…”