Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection

Abstract

Kupffer cells are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/Nuclear Factor of Activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. While their effect on lymphocytes has been studied extensively, there is limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs. Here, we investigated the impact of tacrolimus treatment on innate immunity and more specifically on the capability of Kupffer cells to fight infections. Retrospective analysis of data of more than 2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia, most bacteria were sequestered in liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus‐treated mice. Using imaging we unveiled the mechanism underlying this observation: the reduced capability of Kupffer cells to capture, phagocytose and destroy bacteria in tacrolimus‐treated animals. Further, in a gene expression analysis of infected Kupffer cells, the TREM‐1 pathway was the one with the most significant downregulation after tacrolimus treatment. TREM‐1 inhibition likewise inhibited Kupffer cell bacteria capture. TREM‐1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment. Our results indicate that tacrolimus treatment has a significant impact directly on Kupffer cells and on TREM‐1, thereby compromising their capacity to fend off infections.