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

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.

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

“…Furthermore, a down-regulation of response to metal ions was found which could be related to metallothioneins which protect against oxidative stress and are able to chelate heavy metals [ 71 ]. Both directions of dysregulation were previously observed in liver diseases: While a negative correlation with disease progression was found in hepatocellular carcinoma [ 72 ], a positive correlation was found in most other liver diseases including acetaminophen-induced liver injury [ 73 ]. This indicates that opposite directionality is more plausible based on current literature knowledge, but cannot be fully clarified.…”

Extracellular metallothionein as a therapeutic target in the early progression of type 1 diabetes

“… 12 , 16 UC1MT has also proven effective as a therapeutic treatment when administered in murine models of IBD and AILI, where it interferes with leukocyte infiltration and inflammation. 20 , 24 To determine if UC1MT can block the effects of MT on Th1 and Th2 cell chemotaxis toward their cognate chemokines, Jurkat T cells were exposed to SDF-1α or MT in the presence or absence of UC1MT. We found that preincubation of MT with UC1MT was sufficient to block the chemotactic effect of MT on Jurkat cells, but the antibody did not exert the same effect on SDF-1α mediated chemotaxis ( Figure 5 (a)).…”

“… 9 , 18 This pool of extracellular MT can act as a chemotactic signal and has been implicated in several autoimmune and chronic or acute inflammatory diseases, including inflammatory bowel diseases (IBD), acetaminophen-induced liver injury (AILI), rheumatoid arthritis, multiple sclerosis, and sepsis. 19 , 20 , 21 , 22 , 23 When UC1MT (anti-MT monoclonal antibody) is administered in animal models of IBD 24 and AILI, 20 there is a marked reduction in inflammation and an improvement in disease outcome. In light of the shared inflammatory component of these diseases, we hypothesize that interfering with the pool of extracellular MT may confer therapeutic or protective effects in early-onset T1D.…”

Osteopontin characterizes bile duct–associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis

“…[11] In the liver, tolerance is maintained by resident KCs that dominate the hepatic macrophage pool during steady-state conditions. However, our group and others have shown that KCs are depleted in experimental models for acute liver injury (acetaminophen), [19,20] NAFLD, [21][22][23] hepatocarcinogenesis [19,24,25,] and recently, cholestatic liver disease, [26] while monocytes and monocyte-derived macrophages (MoMFs) infiltrate the liver. During inflammation, monocytes infiltrate the liver and give rise to MoMF that contribute to inflammation, fibrosis, and resolution of disease depending on their phenotype.…”