Dataset Information

Macrophage-derived IL-1? 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-1? is dispensable to AILI, whereas IL-1?, 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-1? in the liver, which is activated by damaged hepatocytes through TLR4/MyD88 signaling. Finally, IL-1? 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-1? in Kupffer cells plays a central role in the immunopathogenesis of AILI and implicates that IL-1? is a promising therapeutic target for AILI treatment.

SUBMITTER: Zhang C

PROVIDER: S-EPMC6207754 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Zhang Chao C Feng Jin J Du Jun J Zhuo Zhiyong Z Yang Shuo S Zhang Weihong W Wang Weihong W Zhang Shengyuan S Iwakura Yoichiro Y Meng Guangxun G Fu Yang-Xin YX Hou Baidong B Tang Hong H

Cellular & molecular immunology 20170515 11

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 inflamm ...[more]

PMID: 28504245

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Project description:Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Dataset Information

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

Publications

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

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