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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Lindsey Devisscher¹  Sanne Van Campenhout¹  Sander Lefere¹  Sarah Raevens²  Laurentijn Tilleman³  Filip Van Nieuwerburgh³  Hannelore P. Van Eeckhoutte²  Anne Hoorens⁴  Michael A. Lynes⁵  Anja Geerts²  Debby Laukens²  Hans Van Vlierberghe² 

[1] Gut-Liver ImmunoPharmacology Unit, Department Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University;Hepatology Research Unit, Department of Gastroenterology and Hepatology, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University;Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University;Department of Pathology, Faculty of Medicine and Health Sciences, Ghent University;Department of Molecular and Cell Biology, University of Connecticut

关键词: acetaminophen;    acute liver injury;    drug-induced liver failure;    hepatic inflammation;    Kupffer cells;    liver immunity;    macrophages;    metallothioneins;    mouse model;    paracetamol;   

DOI  :  10.1002/JLB.3A0820-527R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

CC BY