A research team from School of Basic Medicine and Union Hospital, Tongji Medical College of Huazhong University of Science and Technology (HUST) has uncovered a priorly unknown role of regulatory T cells (Tregs) in the protection against hepatic ischemia-reperfusion (I/R) injury, a common complication of liver surgery and transplantation. Their findings, published in the Journal of Clinical Investigation, identified the TLR4 signaling pathway within Tregs as a critical mediator of liver protection and a promising target for therapeutic intervention.

Hepatic I/R injury occurs when blood flow is temporarily restricted during surgery and then restored, triggering an inflammatory event that can lead to postoperative liver failure. The study, led by Prof. WANG Hui from the School of Basic Medicine and Prof. ZHANG Jinxiang from Union Hospital, found that, in both patients undergoing liver surgery and mouse models, the number of Tregs in the liver was significantly reduced following I/R, and this reduction correlated with the severity of liver injury.

Using mice with Treg-specific deletion of TLR4—a receptor traditionally deemed a driver of inflammation—the researchers made a surprising discovery: TLR4 in Tregs actually helped limit liver damage. Mechanistically, TLR4 activated a signal cascade involving MyD88, ERK, and CREB, which in turn promoted the production of the anti-inflammatory cytokine IL-10. When TLR4 was absent in Tregs, this protective pathway was impaired, resulting in worsened liver injury. Notably, administering exogenous IL-10 reversed the damage, confirming that the pathway played a critical role in the process.

This research challenges the conventional view that TLR4 functions solely as a pro-inflammatory receptor and establishes that the TLR4–IL-10 axis can serve as a potential therapeutic target. The findings give clues to new strategies for preventing and treating perioperative liver injury in procedures such as hepatectomy and liver transplantation.