Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury.
Kupffer cells
acetaminophen
acute liver injury
drug-induced liver failure
hepatic inflammation
liver immunity
macrophages
metallothioneins
mouse model
paracetamol
Journal
Journal of leukocyte biology
ISSN: 1938-3673
Titre abrégé: J Leukoc Biol
Pays: England
ID NLM: 8405628
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
pubmed:
17
3
2021
medline:
8
2
2022
entrez:
16
3
2021
Statut:
ppublish
Résumé
Acetaminophen (APAP) intoxication is the foremost cause of drug-induced liver failure in developed countries. The only pharmacologic treatment option, N-acetylcysteine (NAC), is not effective for patients who are admitted too late and/or who have excessive liver damage, emphasizing the need for alternative treatment options. APAP intoxication results in hepatocyte death and release of danger signals, which further contribute to liver injury, in part by hepatic monocyte/macrophage infiltration and activation. Metallothionein (MT) 1 and 2 have important danger signaling functions and might represent novel therapeutic targets in APAP overdose. Therefore, we evaluated hepatic MT expression and the effect of anti-MT antibodies on the transcriptional profile of the hepatic macrophage population and liver injury following APAP overdose in mice. Hepatic MT expression was significantly induced in APAP-intoxicated mice and abundantly present in human livers. APAP intoxication in mice resulted in increased serum transaminase levels, extended necrotic regions on liver histology and induced expression of proinflammatory markers, which was significantly less pronounced in mice treated with anti-MT antibodies. Anti-MT antibody therapy attenuated proinflammatory macrophage polarization, as demonstrated by RNA sequencing analyses of isolated liver macrophages and in LPS-stimulated bone marrow-derived macrophages. Importantly, NAC and anti-MT antibodies were equally effective whereas administration of anti-MT antibody in combination with NAC exceeded the efficiency of both monotherapies in APAP-induced liver injury (AILI). We conclude that the neutralization of secreted MTs using a monoclonal antibody is a novel therapeutic strategy as mono- or add-on therapy for AILI. In addition, we provide evidence suggesting that MTs in the extracellular environment are involved in macrophage polarization.
Identifiants
pubmed: 33724533
doi: 10.1002/JLB.3A0820-527R
doi:
Substances chimiques
Analgesics, Non-Narcotic
0
Antibodies, Monoclonal
0
Acetaminophen
362O9ITL9D
Metallothionein
9038-94-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
123-133Informations de copyright
©2021 Society for Leukocyte Biology.
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