Recipient toll-like receptor 4 determines the outcome of ischemia-reperfusion injury in steatotic liver transplantation in mice

Abstract

Toll-like receptor 4 (TLR4) plays a crucial role in ischemia-reperfusion injury (IRI) after liver transplantation (LT). However, the role of TLR4 in the context of steatotic grafts remains unclear. In this study, we developed a mouse model to explore IRI mechanisms in steatotic LT using TLR4 knockout mice as recipients. We successfully transplanted steatotic grafts with approximately 35% macrosteatosis and 5 hours of cold storage. Compared to normal LT, steatotic LT resulted in significantly higher serum level of alanine aminotransferase and high mobility group box 1 (HMGB1), higher transcriptional expression of inflammatory markers (C-X-C motif chemokine ligand 2, caspase-1, and caspase-11), and increased infiltration of CD11b-positive cells, correlating with lower survival. Serum HMGB1 and cleaved caspase-3 activation peaked earlier than serum alanine aminotransferase, with cold-stored steatotic grafts releasing more HMGB1. Notably, TLR4 knockout recipients demonstrated improved survival, attenuated inflammatory response, and reduced apoptosis. These findings suggest that TLR4 deficiency in recipients ameliorates IRI in steatotic LT, highlighting the importance of recipient immune modulation in mitigating steatotic graft injury.

Keywords: ischemia-reperfusion injury; liver transplantation; steatotic liver grafts; toll-like receptor 4.