Amphiregulin alleviated concanavalin A-induced acute liver injury via IL-22

Abstract

Objectives

Amphiregulin (Areg), a glycoprotein from the epidermal growth factor receptor (EGFR) ligand family, has a well-documented protective role against tissue injury; however, its effects on immune-mediated liver injury are still unclear. Here, we used a concanavalin A (ConA)-induced acute liver hepatitis model to explore the effects of Areg on immune-mediated acute liver injury.

Materials and methods

Some C57BL/6 mice were administered ConA at a dose of 20 mg/kg (model mice), and some received 5 µg of Areg (treated mice). Then, their survival rates over 36 h were analyzed. After 5 h of treatment, liver function, hepatic histology, and apoptosis in liver tissue were investigated, and cytokine expression and neutrophil infiltration and activity in the liver were detected. Moreover, the protective effects of Areg were also evaluated without IL-22 in vivo.

Results

Our results showed that Areg administration increased acute liver failure (ALF) mouse survival, restored liver function, and alleviated liver damage. Interestingly, Areg administration increased IL-22 production in hepatic T cells and upregulated IL-22 concentrations in the serum and liver, whereas IL-22 neutralization completely abolished the therapeutic effect of Areg. Meanwhile, Areg administration was concomitant with increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, which are important in the hepatoprotective mechanism of IL-22.

Conclusions

Areg showed direct protective effects against ConA-induced acute liver injury, which suggests the potential therapeutic application of Areg in immune-mediated ALF.

Keywords:

• Amphiregulin (Areg)
• concanavalin A (Con A)
• acute liver failure (ALF)
• IL-22
• STAT3

Author contributions

Conceptualization, Yanwen Peng and Qili Wu; formal analysis, Qili Wu and Jingrou Chen; funding acquisition, Yanwen Peng; investigation, Qili Wu, Jingrou Chen, and Yinhong Zhu; methodology, ShujuanXie and Xiaoli Hu; project administration, Yanwen Peng; supervision, Changyou Wu and Zhong Pei; writing-original draft, Yanwen Peng and Qili Wu; writing-review and editing, Yanwen Peng and ShiqiuXiong.

Disclosure statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; collection, analyses, or interpretation of data; writing of the manuscript, or decision to publish the results.

Additional information

Funding

This research was funded by the National Natural Science Foundation of China [grant numbers 81570161 and 31701116], the Key Scientific and Technological Projects of Guangdong Province [grant number 2016B030229002], the Natural Science Foundation of Guangdong Province [grant number 2015A030312013], the Key Scientific and Technological Program of Guangzhou City [grant number 201704020223], the Key-Area Research and Development Program of Guangdong Province [grant number 2019B020236004, 2019B020235002], and the Southern China International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases [grant number 2015B050501003].