Hepatic vagotomy blunts liver regeneration after hepatectomy by downregulating the expression of interleukin-22

Heng Zhou; Ju-Ling Xu; San-Xiong Huang; Ying He; Xiao-Wei He; Sheng Lu; Bin Yao

doi:10.4240/wjgs.v15.i12.2866

Hepatic vagotomy blunts liver regeneration after hepatectomy by downregulating the expression of interleukin-22

World J Gastrointest Surg. 2023 Dec 27;15(12):2866-2878. doi: 10.4240/wjgs.v15.i12.2866.

Authors

Heng Zhou¹, Ju-Ling Xu², San-Xiong Huang³, Ying He⁴, Xiao-Wei He¹, Sheng Lu¹, Bin Yao⁵

Affiliations

¹ Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China.
² Department of Medicine, Medical School of Huzhou University, Huzhou 313000, Zhejiang Province, China.
³ Department of Hepatobiliary Surgery, The First People's Hospital of Huzhou, Huzhou 313000, Zhejiang Province, China.
⁴ Zhejiang Provincial Key Laboratory of Media Biology and Pathogenic Control, Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China.
⁵ Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China. 50228@zjhu.edu.cn.

Abstract

Background: Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy (PHx). At present, there is a lack of recognized safe, effective, and stable drugs to promote liver regeneration. It has been reported that vagus nerve signaling is beneficial to liver regeneration, but the potential mechanism at play here is not fully understood.

Aim: To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.

Methods: A PHx plus hepatic vagotomy (Hv) mouse model was established. The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice. In order to further investigate the role of interleukin (IL)-22 in liver regeneration inhibition mediated by Hv, the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured. The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.

Results: Compared to control-group mice, Hv mice showed severe liver injury and weakened liver regeneration after PHx. Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3 (STAT3) pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx. Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury, while treatment with IL-22 binding protein (an inhibitor of IL-22 signaling) reduce the concentration of IL-22 induced by PHx, inhibits the activation of the STAT3 signaling pathway in the liver after PHx, thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.

Conclusion: Hv attenuates liver regeneration after hepatectomy, and the mechanism may be related to the fact that Hv downregulates the production of IL-22, then blocks activation of the STAT3 pathway.

Keywords: Hepatic vagotomy; Interleukin-22; Interleukin-22 binding protein; Liver regeneration; Partial hepatectomy; Signal transducer and activator of transcription 3.