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β-arrestin2 deficiency ameliorates S-100-induced autoimmune hepatitis in mice by inhibiting infiltration of monocyte-derived macrophage and attenuating hepatocyte apoptosis

Acta Pharmacologica Sinica volume 44, pages 2048–2064 (2023)Cite this article

Abstract

Autoimmune hepatitis (AIH) is a progressive hepatitis syndrome characterized by high transaminase levels, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies. Misdiagnosis or delayed treatment of AIH can lead to cirrhosis or liver failure, which poses a major risk to human health. β-Arrestin2, a key scaffold protein for intracellular signaling pathways, has been found to be involved in many autoimmune diseases such as Sjogren’s syndrome and rheumatoid arthritis. However, whether β-arrestin2 plays a role in AIH remains unknown. In the present study, S-100-induced AIH was established in both wild-type mice and β-arrestin2 knockout (Arrb2 KO) mice, and the experiments identified that liver β-arrestin2 expression was gradually increased, and positively correlated to serum ANA, ALT and AST levels during AIH progression. Furthermore, β-arrestin2 deficiency ameliorated hepatic pathological damage, decreased serum autoantibody and inflammatory cytokine levels. β-arrestin2 deficiency also inhibited hepatocyte apoptosis and prevented the infiltration of monocyte-derived macrophages into the damaged liver. In vitro experiments revealed that β-arrestin2 knockdown suppressed the migration and differentiation of THP-1 cells, whereas β-arrestin2 overexpression promoted the migration of THP-1 cells, which was regulated by the activation of the ERK and p38 MAPK pathways. In addition, β-arrestin2 deficiency attenuated TNF-α-induced primary hepatocyte apoptosis by activating the Akt/GSK-3β pathway. These results suggest that β-arrestin2 deficiency ameliorates AIH by inhibiting the migration and differentiation of monocytes, decreasing the infiltration of monocyte-derived macrophages into the liver, thereby reducing inflammatory cytokines-induced hepatocytes apoptosis. Therefore, β-arrestin2 may act as an effective therapeutic target for AIH.

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Fig. 1: Expression of β-arrestin2 increased in liver during autoimmune hepatitis (AIH) development.
Fig. 2: β-arrestin2 deficiency ameliorates AIH in mice.
Fig. 3: β-arrestin2 deficiency reduces hepatocyte apoptosis in AIH.
Fig. 4: β-arrestin2 deficiency inhibits inflammation and infiltration of monocyte-derived macrophages in AIH.
Fig. 5: β-arrestin2 plays a crucial role in THP-1 monocyte migration.
Fig. 6: β-arrestin2 regulates the migration of THP-1 monocytes via ERK and p38 MAPK signaling pathways.
Fig. 7: Silencing of β-arrestin2 inhibits differentiation of THP-1 cells to macrophages and reduces hepatocyte apoptosis induced by TNF-α secreted from macrophages.
Fig. 8: Deletion of β-arrestin2 reduces apoptosis of primary hepatocytes by activating the Akt/GSK-3β pathway.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81770605), the Research Level Improvement Program of Anhui Medical University (No. 2021xkjT016), the Research Fund of Anhui Institute of Translational Medicine (No. 2022zhyx-C07), the Program of Basic and Clinical Collaborative Research (No. 2022sfy014). We acknowledge the help of the staff members of the Institute of Clinical Pharmacology, Anhui Medical University in conducting the study.

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  1. These authors contributed equally: Ting-ting Chen, Xiu-qin Li

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China

    Ting-ting Chen, Xiu-qin Li, Nan Li, Ya-ping Xu, Yu-han Wang, Zi-ying Wang, Sheng-nan Zhang, Meng Qi, Shi-hao Zhang, Wei Wei & Wu-yi Sun

  2. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Hua Wang

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Contributions

WYS, HW and WW contributed to conception and experiment design; TTC, XQL, NL, YPX, YHW, ZYW, MQ and SNZ performed the experiments under the supervision of WYS and WW; TTC and XQL analyzed the data, and drafted the manuscript; WYS, SHZ and HW revised the manuscript. All authors have confirmed the submission of this manuscript.

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Correspondence to Wei Wei, Hua Wang or Wu-yi Sun.

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Chen, Tt., Li, Xq., Li, N. et al. β-arrestin2 deficiency ameliorates S-100-induced autoimmune hepatitis in mice by inhibiting infiltration of monocyte-derived macrophage and attenuating hepatocyte apoptosis. Acta Pharmacol Sin 44, 2048–2064 (2023). https://doi.org/10.1038/s41401-023-01103-9

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