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Rôle de l'alarmine IL-33 dans un modèle murin d'ischémie- reperfusion hépatique

Abstract : Introduction: Interleukin (IL)-33 plays a role as an alarmin in the initiation of the inflammatory response in renal ischemia/reperfusion (I/R) injury, involving invariant natural killer T (iNKT) cells. Aims: The aim of this study was to establish whether IL-33 also acts as an alarmin in hepatic I/R injury and to explore the contribution of IL-33 and iNKT cells in the recruitment of neutrophil granulocytes and monocytes/macrophages after I/R. Methods: A model of warm hepatic ischemia with clamping of 70% of the liver was chosen in wildtype mice, IL-33 knock out (KO) mice and iNKT cell-deficient (Jα18 KO) mice with C57BL/6 background. Severity of I/R injury was assessed by plasma alanin-aminotransferase (ALT) measurement and histological analysis. Interleukin-33 was measured in blood and in liver by ELISA (enzyme-linked immunosorbent assay ) and western blot while IL-33 neo synthesis was measured by RT-qPCR (reverse transcriptase- quantitative polymerase chain reaction). The recruitment of immune cells in liver after I/R was analyzed by flow cytometry. Results: In wild-type mice, IL-33 was constitutively expressed in liver endothelial cells of the sinusoids and of the portal venules, and was released from the ischemic phase and its immediate course into systemic circulation without neo-synthesis. I/R injury was decreased in IL-33-deficient mice after 4 hours of reperfusion, comparing to wild type mice. Therefore, in the first hours after ischemia, IL-33 acts as an alarmin and is at least partly responsible for I/R injury. I/R injury was also decreased in iNKT cell-deficient mice after 4 hours while in wild-type mice, iNKT cells were found activated in periphery (spleen) and recruited locally. Neutrophil granulocytes and monocytes/macrophages were recruited in the liver after one hour of reperfusion in wild type mice, whereas this recruitment was decreased in IL-33-deficient mice and in iNKT cell-deficient mice. These findings along with the fact that recruitment of iNKT cells was significantly decreased in IL-33 deficient mice, as compared to WT, lead to propose that an IL-33/iNKT cell axis mediates the early stages of inflammation in I/R liver injury. Conclusion: Interleukin-33, as an alarmin, early contributes to I/R liver injuries. It could act by recruiting iNKT cells that would in turn amplify the recruitment of immuno-inflammatory cells together with IL-33. Interleukin-33 hence represents a major potential therapeutic target to decrease I/R injury in liver transplantation.
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Louise Barbier. Rôle de l'alarmine IL-33 dans un modèle murin d'ischémie- reperfusion hépatique. Organisation et fonctions cellulaires [q-bio.SC]. Université de Poitiers - Faculté des Sciences Fondamentales et Appliquées, 2019. Français. ⟨tel-02471751v1⟩

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