Abstract
Acute liver failure (ALF) is a deadly clinical disorder with few effective treatments and unclear pathogenesis. In our previous study, we demonstrated that aberrant Wnt5a expression was involved in acute-on-chronic liver failure. However, the role of Wnt5a in ALF is unknown. We investigated the expression of Wnt5a and its downstream c-Jun N-terminal kinase (JNK) signaling in a mouse model of ALF established by coinjection of D-galactosamine (D-Gal) and lipopolysaccharide (LPS) in C57BL/6 mice. We also investigated the role of Box5, a Wnt5a antagonist, in vivo. Moreover, the effect of Wnt5a/JNK signaling on downstream inflammatory cytokine expression, phagocytosis, and migration in THP-1 macrophages was studied in vitro. Aberrant Wnt5a expression and JNK activation were detected in D-Gal/LPS-induced ALF mice. Box5 pretreatment reversed JNK activation and eventually decreased the mortality rate of D-Gal/LPS-treated mice, with reduced hepatic necrosis and apoptosis, serum ALT and AST levels, and liver inflammatory cytokine expression, although the latter was not significant. We further demonstrated that recombinant Wnt5a (rWnt5a)-induced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA expression and increased THP-1 macrophage phagocytosis in a JNK-dependent manner, which could be restored by Box5. In addition, rWnt5a-induced migration of THP-1 macrophages was also reversed by Box5. Our findings suggested that Wnt5a/JNK signaling plays an important role in the development of ALF and that Box5 could have particular hepatoprotective effects in ALF.
Highlights
Acute liver failure (ALF) is a serious life-threatening syndrome characterized by abrupt hepatocyte necrosis, which results in altered coagulation and mentation [1]
RWnt5a-induced migration of THP-1 macrophages was turned by Box5
With the use of haematoxylin and eosin (H&E) and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, we found that hepatocellular necrosis and apoptosis occurred more in the mice of D-Gal/LPS group than that in Control group (Fig. 1a and 1b)
Summary
Acute liver failure (ALF) is a serious life-threatening syndrome characterized by abrupt hepatocyte necrosis, which results in altered coagulation and mentation [1]. Due to rapid progression to multiorgan failure and devastating complications, ALF is a disorder with high mortality and resource cost. The mainstay of ALF management is supportive care and liver transplantation [2]. Liver transplantation is the determined cure for ALF, extensions are challenged by availability of suitable organs, high costs and sufferings from the rejection after transplantation. It is generally believed that ALF is associated with direct cellular damage caused by viruses, drugs and other uncommon sources, as well as more importantly, immune-mediated inflammatory injury [4, 5]. Many studies indicated that the dysfunction of monocytes and macrophages along with their induced inflammatory cytokines play significant roles in the initiation and progression of ALF [6, 7]
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