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Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury

(2022) JOURNAL OF LEUKOCYTE BIOLOGY. 111(1). p.123-133
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Abstract
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.
Keywords
acetaminophen, acute liver injury, drug&#8208, induced liver failure, hepatic inflammation, Kupffer cells, liver immunity, macrophages, metallothioneins, mouse model, paracetamol

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MLA
Devisscher, Lindsey, et al. “Metallothioneins Alter Macrophage Phenotype and Represent Novel Therapeutic Targets for Acetaminophen-Induced Liver Injury.” JOURNAL OF LEUKOCYTE BIOLOGY, vol. 111, no. 1, 2022, pp. 123–33, doi:10.1002/JLB.3A0820-527R.
APA
Devisscher, L., Van Campenhout, S., Lefere, S., Raevens, S., Tilleman, L., Van Nieuwerburgh, F., … Van Vlierberghe, H. (2022). Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury. JOURNAL OF LEUKOCYTE BIOLOGY, 111(1), 123–133. https://doi.org/10.1002/JLB.3A0820-527R
Chicago author-date
Devisscher, Lindsey, Sanne Van Campenhout, Sander Lefere, Sarah Raevens, Laurentijn Tilleman, Filip Van Nieuwerburgh, Hannelore P. Van Eeckhoutte, et al. 2022. “Metallothioneins Alter Macrophage Phenotype and Represent Novel Therapeutic Targets for Acetaminophen-Induced Liver Injury.” JOURNAL OF LEUKOCYTE BIOLOGY 111 (1): 123–33. https://doi.org/10.1002/JLB.3A0820-527R.
Chicago author-date (all authors)
Devisscher, Lindsey, Sanne Van Campenhout, Sander Lefere, Sarah Raevens, Laurentijn Tilleman, Filip Van Nieuwerburgh, Hannelore P. Van Eeckhoutte, Anne Hoorens, Michael A. Lynes, Anja Geerts, Debby Laukens, and Hans Van Vlierberghe. 2022. “Metallothioneins Alter Macrophage Phenotype and Represent Novel Therapeutic Targets for Acetaminophen-Induced Liver Injury.” JOURNAL OF LEUKOCYTE BIOLOGY 111 (1): 123–133. doi:10.1002/JLB.3A0820-527R.
Vancouver
1.
Devisscher L, Van Campenhout S, Lefere S, Raevens S, Tilleman L, Van Nieuwerburgh F, et al. Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury. JOURNAL OF LEUKOCYTE BIOLOGY. 2022;111(1):123–33.
IEEE
[1]
L. Devisscher et al., “Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury,” JOURNAL OF LEUKOCYTE BIOLOGY, vol. 111, no. 1, pp. 123–133, 2022.
@article{8703767,
  abstract     = {{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.}},
  author       = {{Devisscher, Lindsey and Van Campenhout, Sanne and Lefere, Sander and Raevens, Sarah and Tilleman, Laurentijn and Van Nieuwerburgh, Filip and Van Eeckhoutte, Hannelore P. and Hoorens, Anne and Lynes, Michael A. and Geerts, Anja and Laukens, Debby and Van Vlierberghe, Hans}},
  issn         = {{0741-5400}},
  journal      = {{JOURNAL OF LEUKOCYTE BIOLOGY}},
  keywords     = {{acetaminophen,acute liver injury,drug&#8208,induced liver failure,hepatic inflammation,Kupffer cells,liver immunity,macrophages,metallothioneins,mouse model,paracetamol}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{123--133}},
  title        = {{Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury}},
  url          = {{http://dx.doi.org/10.1002/JLB.3A0820-527R}},
  volume       = {{111}},
  year         = {{2022}},
}

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