Korean J Transplant.  2023 Nov;37(Suppl 1):S284. 10.4285/ATW2023.F-8988.

Tet2-mediated macrophage activation promotes liver regeneration

• Chen Y
• Meng L
• Xu N
• Wang S
• Xu X

• KMID: 2551913
• DOI: http://doi.org/10.4285/ATW2023.F-8988

Abstract

Background
Macrophages are predominant immune cells that secret interleukin 6 (IL-6) and hepatocyte growth factor to promote liver regeneration after liver resection. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates the secretion of pro-inflammatory factors in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration.
Methods
A 70% partial hepatectomy mice model was established. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescences, and flow cytometry were performed to explore the infiltration and phenotypes of immune cells in mice models. Molecular dynamics simulations were carried out to study the interaction of Tet2 with Stat1.
Results
We found Tet2 in macrophages negatively regulates liver regeneration in the partial hepatectomy mice model. In mechanism, Tet2 interacts with Stat1 to inhibit the expressions of proinflammatory factors and suppress liver regeneration. Tet2 inhibitor BC339 attenuated the interaction of Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. Notably, Tet2 also directly affected hepatocyte proliferation, independent of the IL-6-Stat3 signaling pathway.
Conclusions
Tet2 in macrophages negatively regulates liver regeneration via interacting with Stat1. Our results suggest that specific targeting Tet2 in macrophages promotes the recovery of liver function after hepatectomy.