Inhibition of Drug-Induced Liver Injury in Mice Using a Positively Charged Peptide That Binds DNA.

Autor: Marques PE; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.; Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil., Vandendriessche S; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., de Oliveira THC; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.; Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil., Crijns H; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Lopes ME; Center for Gastrointestinal BiologyDepartment of MorphologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil., Blanter M; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Schuermans S; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Yu K; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Poosti F; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Vanheule V; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Janssens R; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium., Boff D; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.; Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil., Kungl AJ; Department of Pharmaceutical ChemistryInstitute of Pharmaceutical SciencesKarl-Franzens UniversitätGrazAustria., Menezes GB; Center for Gastrointestinal BiologyDepartment of MorphologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil., Teixeira MM; Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil., Proost P; Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2021 Oct; Vol. 5 (10), pp. 1737-1754. Date of Electronic Publication: 2021 Jul 01.
DOI: 10.1002/hep4.1759
Abstrakt: Hepatic cell death occurs in response to diverse stimuli such as chemical and physical damage. The exposure of intracellular contents such as DNA during necrosis induces a severe inflammatory response that has yet to be fully explored therapeutically. Here, we sought means to neutralize the ability of extracellular DNA to induce deleterious tissue inflammation when drug-induced liver injury had already ensued. DNA exposure and inflammation were investigated in vivo in drug-induced liver injury using intravital microscopy. The necrotic DNA debris was studied in murine livers in vivo and in DNA debris models in vitro by using a positively charged chemokine-derived peptide (MIG30; CXCL9[74-103]). Acetaminophen-induced liver necrosis was associated with massive DNA accumulation, production of CXC chemokines, and neutrophil activation inside the injured tissue. The MIG30 peptide bound the healthy liver vasculature and, to a much greater extent, to DNA-rich necrotic tissue. Moreover, MIG30 bound extracellular DNA directly in vivo in a charge-dependent manner and independently of glycosaminoglycans and chemokines. Post-treatment of mice with MIG30 reduced mortality, liver damage, and inflammation significantly. These effects were not observed with a control peptide that does not bind DNA. Mechanistically, MIG30 inhibited the interaction between DNA and histones, and promoted the dissociation of histones from necrotic debris. MIG30 also inhibited the pro-inflammatory effect of CpG DNA, as measured by a reduction in CXCL8 production, indicating that MIG30 disturbs the ability of DNA to induce hepatic inflammation. Conclusion: The use of DNA-binding peptides reduces necrotic liver injury and inflammation, even at late timepoints.
(© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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