The GAG-Binding Peptide MIG30 Protects against Liver Ischemia-Reperfusion in Mice

Ischemia-reperfusion injury (IRI) drives graft rejection and is the main cause of mortality after liver transplantation. During IRI, an intense inflammatory response marked by chemokine production and neutrophil recruitment occurs. However, few strategies are available to restrain this excessive res...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-09, Vol.23 (17), p.9715
Main Authors: Oliveira, Thiago Henrique Caldeira, Vanheule, Vincent, Vandendriessche, Sofie, Poosti, Fariba, Teixeira, Mauro Martins, Proost, Paul, Gouwy, Mieke, Marques, Pedro Elias
Format: Article
Language:English
Subjects:
Binding
Chemokines
Cytokines
Endothelium
Glycosaminoglycans
Graft rejection
Heparan sulfate
Immune system
Inflammation
Inflammatory response
Interleukin 6
Ischemia
ischemia-reperfusion
Leukocytes (neutrophilic)
Lipopolysaccharides
Liver
Liver diseases
Neutrophils
Peptides
Recruitment
Reperfusion
Transplantation
Tumor necrosis factor-α
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Summary:Ischemia-reperfusion injury (IRI) drives graft rejection and is the main cause of mortality after liver transplantation. During IRI, an intense inflammatory response marked by chemokine production and neutrophil recruitment occurs. However, few strategies are available to restrain this excessive response. Here, we aimed to interfere with chemokine function during IRI in order to disrupt neutrophil recruitment to the injured liver. For this, we utilized a potent glycosaminoglycan (GAG)-binding peptide containing the 30 C-terminal amino acids of CXCL9 (MIG30) that is able to inhibit the binding of chemokines to GAGs in vitro. We observed that mice subjected to IRI and treated with MIG30 presented significantly lower liver injury and dysfunction as compared to vehicle-treated mice. Moreover, the levels of chemokines CXCL1, CXCL2 and CXCL6 and of proinflammatory cytokines TNF-α and IL-6 were significantly reduced in MIG30-treated mice. These events were associated with a marked inhibition of neutrophil recruitment to the liver during IRI. Lastly, we observed that MIG30 is unable to affect leukocytes directly nor to alter the stimulation by either CXCL8 or lipopolysaccharide (LPS), suggesting that its protective properties derive from its ability to inhibit chemokine activity in vivo. We conclude that MIG30 holds promise as a strategy to treat liver IRI and inflammation.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23179715