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Noncanonical Wnt5a/JNK Signaling Contributes to the Development of D-Gal/LPS-Induced Acute Liver Failure

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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.

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Funding

This work was supported by the National Natural Science Foundation of China (81970522), the Shandong University Multidisciplinary Research and Innovation Team of Young Scholars (2020QNQT11), the China Postdoctoral Science Foundation (2020M672074), the Young Taishan Scholars (tsqn202103169), the Natural Science Foundation of Shandong Province (ZR2019PH104), and the Scientific Research Foundation of Qilu Hospital of Shandong University (Qingdao) (QDKY2017QN13).

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Authors and Affiliations

  1. Department of Hepatology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, China

    Xiang-Fen Ji, Fei Sun & Jing-Wei Wang

  2. Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China

    Yu-Chen Fan & Kai Wang

  3. Institute of Hepatology, Shandong University, Jinan, 250012, China

    Yu-Chen Fan & Kai Wang

  4. Hepatology Institute of Shandong University, Wenhuaxi Road 107#, 250012, Jinan, Shandong, China

    Kai Wang

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  1. Xiang-Fen Ji
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Contributions

Xiang-Fen Ji designed the study, carried out the experiments, and wrote the first draft of the manuscript. Fei Sun performed some experiments. Jing-Wei Wang analyzed some data. Yu-Chen Fan analyzed some data and was involved in editing the manuscript. Kai Wang revised the manuscript critically for important intellectual content.

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Correspondence to Kai Wang.

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All the animal experiments were approved by the Ethical Committee of Qilu Hospital (Qingdao), Shandong University.

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Ji, XF., Fan, YC., Sun, F. et al. Noncanonical Wnt5a/JNK Signaling Contributes to the Development of D-Gal/LPS-Induced Acute Liver Failure. Inflammation 45, 1362–1373 (2022). https://doi.org/10.1007/s10753-022-01627-y

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