Immunomodulation by lactate and the IL-33/ST2 axis in hepatic ischemia reperfusion syndrome and its resolution

Organ Ischemy Reperfusion (IR) Syndrome is being studied in our laboratory as a model of acute sterile inflammation, as part of both basic and medical research in organ transplantation. Organ IR is characterized by a large leukocyte infiltrate and severe tissue damage whose initiator and resolution signals remain poorly described to date. Among these signals, our laboratory focuses on the alarmine IL-33 and lactate.

For example, we have demonstrated in mouse models that a key mechanism responsible for tissue damage associated with an IR sequence in the kidney (Ferhrat et al, 2018 doi: 10.1681/ASN.2017060650) and liver (Barbier et al, 2021 doi: 10.3389/fimmu.2021.744927) is the biological axis consisting of alarmin IL-33 (and its ST2 receptor) and innate T cells (ITC) called iNKT (for "invariant T cells").

Lactate, long considered a by-product of metabolism, is now recognized as a major energy source and a versatile signalling molecule that regulates immune cell metabolism, gene expression and intercellular communication. A recent study documents that lactate intake prior to liver IR protects hepatocytes by suppressing neutrophil-induced inflammation and disrupting hepatocyte-neutrophil communication across the IL-33/ST2 axis (Fang et al., 2026 doi: 10.1186/s12964-026-02662-0). In addition, our preliminary data using the MCT1+/- lactate transporter heterozygous murine line support a protective role for hepatic IR.

The aim of our project is to investigate the mechanisms underlying the protective action of lactate in liver IR, focusing on its impact on lymphoid (Treg and ITC) and myeloid cells (M2 macrophages, Kupffer cells) during liver reperfusion and repair phases.

Methods:

In order to carry out this project, in addition to the access to the ImageUP platform materials (imaging and flow cytometry), our laboratory will make available the following models and expertise:

• Murine models of hepatic I/R and analysis of liver suffering using different techniques: ALT/ASAT assays, immunohistochemistry, assessment of fibrosis, etc…
• Transgenic mouse lines available: IL-33 KO, ST2 KO and MCT1^fl/fl, currently being acquired: Cre-ert 2 tamoxifen.
• Culture of primary murine hepatocytes.
• Hypoxia chamber, metabolic flux measurements (Seahorse).
• Human hepatocyte cell lines HepG2 and HepaRG; mononuclear cells of human peripheral blood.
• Expertise in multiparameter spectral flow cytometry for immune cell analysis.
• Biochemistry and basic molecular biology techniques: Western blot, RT-qPCR, immunofluorescence, etc…

The laboratory “Ischémie Reperfusion, Métabolisme et Inflammation Stérile en Transplantation” (IRMETIST) is a joint research unit INSERM (U1313)/University of Poitiers (located between Paris and Bordeaux, 1h30 by train). The unit is an integral part of the Federal Institute for Biohealth Research. Currently located in two sites, one part of the unit is located on the Poitiers CHU site near the Faculty of Medicine and Pharmacy and the other part is located at the Health Biology (PBS) pole on the campus of the University of Poitiers. The PhD student will work on the PBS site and will benefit from a stimulating environment close to the other IFR BioHealth laboratories and with privileged access to campus platforms.

The research themes of the unit revolve around the improvement of organ transplantation conditions and the study of IR-related injury phenomena. In this context, the IRATI Group makes its expertise in basic and clinical immunology available for the unit’s projects. His main area of activity is the study of innate T cells related to the alarmine cytokine IL-33 in normal and pathological situations.

The candidate must hold a Master’s degree in cell biology and/or immunology. He/she must have a good knowledge of cellular immunology and, if possible, flow cytometry.

The candidate must demonstrate a high level of research motivation, autonomy, methodological rigour, scientific curiosity and initiative.

Training in animal testing would be appreciated. Proficiency in reading, writing and speaking English as well as writing skills are required.