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Dendritic cell depletion exacerbates acetaminophen hepatotoxicity.
Michael K Connolly1, Diego Ayo, Ashim Malhotra
1S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
Hepatology (Baltimore, Md.)
|May 17, 2011
Summary
Dendritic cells (DCs) in the liver protect against acetaminophen (APAP) toxicity. Depleting these immune cells worsens APAP-induced liver injury and mortality, highlighting DCs as crucial in managing APAP overdose effects.
Area of Science:
- Immunology
- Hepatology
- Toxicology
Background:
- Acetaminophen (APAP) overdose is a leading cause of acute liver failure in the US.
- APAP hepatotoxicity is mainly due to toxic metabolites and glutathione depletion.
- Innate immune cells, including dendritic cells (DCs), are implicated in APAP-induced liver injury.
Purpose of the Study:
- To investigate the role of dendritic cells (DCs) in modulating acetaminophen (APAP)-induced hepatotoxicity.
- To determine if DCs influence intrahepatic inflammation and liver damage following APAP overdose.
Main Methods:
- Mice were challenged with APAP overdose.
- Dendritic cell (DC) depletion was induced using specific antibodies.
- DC immune-phenotype, cytokine production, and immune cell activation were analyzed.
- Mice received FMS-like tyrosine kinase 3 ligand (Flt3L) for endogenous DC expansion.
- Mortality and liver injury severity were assessed in treated and control groups.
Main Results:
- APAP challenge altered liver DC immune-phenotype, increasing MHC II, costimulatory molecules, and TLRs.
- Liver DCs produced increased IL-6, MCP-1, and TNF-α post-APAP challenge.
- DC depletion exacerbated APAP-induced liver necrosis and mortality.
- Endogenous DC expansion with Flt3L protected against APAP liver injury.
- APAP-challenged liver DCs inhibited NK cell activation and promoted neutrophil apoptosis.
Conclusions:
- Liver dendritic cells (DCs) play a protective role against acetaminophen (APAP) toxicity.
- Depletion of liver DCs exacerbates APAP-induced hepatotoxicity and mortality.
- DCs modulate immune responses, including NK cell and neutrophil activity, to mitigate APAP liver injury.
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