Reversal of endotoxin tolerance through Liver-X-receptor dependent immunomodulation

• Applicants: Professor Dr. Mihai G. Netea; Katarzyna Placek, Ph.D.; Yahya Sohrabi, Ph.D.
• Subject Area: Immunology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544199135

Sepsis is a life-threatening medical emergency caused by a dysregulated host response to infection. Exposure of the host to repeated endotoxin doses induces an immunosuppressive state, which makes them more susceptible to infectious diseases. Due to the high mortality of sepsis, restoring the balance in the immune responses either by modulating hyperinflammatory reactions or reversing the immune paralysis later in the disease has gained growing interest. A novel approach to treat endotoxin tolerance has derived from recent evidence describing the existence of immune memory in innate immune cells, called trained immunity. This memory enables the cells to show an increased response/enhanced functionality following a secondary challenge. Our previous data demonstrated that activation of Liver-X-Receptors (LXR) induces trained immunity in human monocytes via metabolic regulation. Our preliminary results show that treatment of LPS-tolerized human monocytes with LXR agonists restores the inflammatory response to a secondary stimulation with LPS, indicating that LXR signaling is capable of reversing endotoxin tolerance. In this project, we aim to investigate molecular mechanisms of the reversal of endotoxin tolerance via LXR activation. Our ultimate goal is to develop an immunomodulatory treatment for sepsis that can contribute to the improvement of sepsis outcome in the significant proportion of patients characterized by immune paralysis. We consider LXR signaling to be a highly promising target for novel therapeutic approaches to prevent complications associated with sepsis. To meet our goals we will perform comprehensive studies on relevant signaling pathways and evaluate the effect of LXR activation on metabolic and epigenetic changes in human monocytes in vitro and ex vivo and in clinical settings.

• DFG Programme: Research Grants
• International Connection: Czech Republic, Netherlands
• Cooperation Partners: Professor Dr. Vaclav Horejsi; Professor Leo Joosten, Ph.D.