Related Experiment Video
Updated: Dec 14, 2025
Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen
Published on: November 27, 2019
The Receptor for Advanced Glycation Endproducts (RAGE) Contributes to Severe Inflammatory Liver Injury in Mice
Toni Weinhage1, Timo Wirth2, Paula Schütz1
1Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany.
Abstract:
Background: The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in a number of processes and disorders. While it is known that RAGE-signaling can contribute to toxic liver damage and fibrosis, its role in acute inflammatory liver injury and septic multiorgan failure is yet undefined. We examined RAGE in lipopolysaccharide (LPS) induced acute liver injury of D-galN sensitized mice as a classical model for tumor necrosis factor alpha (TNF-α) dependent inflammatory organ damage. Methods: Mice (Rage-/- and C57BL/6) were intraperitoneally injected with D-galN (300 mg/kg) and LPS (10 μg/kg). Animals were monitored clinically, and cytokines, damage associated molecular pattern molecules (DAMPs) as well as liver enzymes were determined in serum. Liver histology, hepatic cytokines as well as RAGE mRNA expression were analyzed. Cellular activation and functionality were evaluated by flow cytometry both in bone marrow- and liver-derived cells. Results: Genetic deficiency of RAGE significantly reduced the mortality of mice exposed to LPS/D-galN. Hepatocyte damage markers were reduced in Rage-/- mice, and liver histopathology was less severe. Rage-/- mice produced less pro-inflammatory cytokines and DAMPs in serum and liver. While immune cell functions appeared normal, TNF-α production by hepatocytes was reduced in Rage-/- mice. Conclusions: We found that RAGE deletion attenuated the expression of pro-inflammatory cytokines and DAMPs in hepatocytes without affecting cellular immune functions in the LPS/D-galN model of murine liver injury. Our data highlight the importance of tissue-specific RAGE-signaling also in acute inflammatory liver stress contributing to sepsis and multiorgan failure.
Insights
Genetic deficiency of the receptor for advanced glycation end products (RAGE) reduced mortality in a mouse model of acute liver injury. RAGE deletion attenuated inflammatory cytokines and damage-associated molecular patterns in hepatocytes.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- The receptor for advanced glycation end products (RAGE) is implicated in various disorders.
- RAGE signaling contributes to liver damage and fibrosis.
- Its role in acute inflammatory liver injury and sepsis-induced organ failure is unclear.
Purpose of the Study:
- To investigate the role of RAGE in lipopolysaccharide (LPS)-induced acute liver injury in D-galN sensitized mice.
- To determine the impact of RAGE deficiency on inflammatory responses and organ damage in this model.
Main Methods:
- Utilized a murine model of acute liver injury induced by D-galN and LPS.
- Compared wild-type and RAGE-deficient (Rage-/-) mice.
- Assessed mortality, serum markers (cytokines, DAMPs, liver enzymes), liver histology, hepatic cytokines, and RAGE mRNA expression.
Main Results:
- RAGE deficiency significantly reduced mortality and liver injury severity.
- Rage-/- mice exhibited lower levels of pro-inflammatory cytokines and DAMPs in serum and liver.
- Hepatocyte TNF-α production was reduced in Rage-/- mice, while immune cell functions remained largely unaffected.
Conclusions:
- RAGE deletion attenuates pro-inflammatory cytokine and DAMP expression in hepatocytes during acute liver injury.
- Tissue-specific RAGE signaling is crucial in acute inflammatory liver stress, contributing to sepsis and multiorgan failure.
- Targeting RAGE may offer therapeutic potential for inflammatory liver conditions.
