AUTHOR=Barbier Louise , Robin Aurélie , Sindayigaya Rémy , Ducousso Héloïse , Dujardin Fanny , Thierry Antoine , Hauet Thierry , Girard Jean-Philippe , Pellerin Luc , Gombert Jean-Marc , Herbelin André , Salamé Ephrem 

TITLE=Endogenous Interleukin-33 Acts as an Alarmin in Liver Ischemia-Reperfusion and Is Associated With Injury After Human Liver Transplantation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.744927

DOI=10.3389/fimmu.2021.744927

ISSN=1664-3224

ABSTRACT=Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation.
First, a model of warm hepatic ischemia/reperfusion was used in wild type and IL-33-deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic post-reperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring>6), renal failure and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neo-synthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including post-reperfusion syndrome, post-transplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cut-off of IL-33 at 73 pg/mL after reperfusion (73% sensitivity, area under curve 0.76).
Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its closely association with cardinal features of early liver injury-associated disorders in LT patients.