Inhibition of Drug‐Induced Liver Injury in Mice Using a Positively Charged Peptide That Binds DNA
| Autor: | Mauro M. Teixeira, Sofie Vandendriessche, Gustavo B. Menezes, Helena Crijns, Sara Schuermans, Daiane Boff, Vincent Vanheule, Paul Proost, Pedro Elias Marques, Thiago H.C. de Oliveira, Marfa Blanter, Mateus Eustáquio Lopes, Rik Janssens, Karen Yu, Fariba Poosti, Andreas J. Kungl |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Necrosis
Static Electricity ACETAMINOPHEN-INDUCED HEPATOTOXICITY Anti-Inflammatory Agents Inflammation RC799-869 Chemokine CXCL9 Neutrophil Activation Histones chemistry.chemical_compound Mice INFLAMMATION In vivo medicine Animals Humans NEUTROPHILS Acetaminophen Liver injury Science & Technology Gastroenterology & Hepatology Hepatology biology Interleukin-8 DNA Degradation Necrotic TRAPS Original Articles Diseases of the digestive system. Gastroenterology medicine.disease Cell biology Extracellular Matrix Disease Models Animal Histone CELL-DEATH CHEMOKINES chemistry Liver Hepatic stellate cell biology.protein Original Article medicine.symptom Chemical and Drug Induced Liver Injury Peptides Life Sciences & Biomedicine Chemokines CXC Intracellular DNA |
| Zdroj: | Hepatology Communications, Vol 5, Iss 10, Pp 1737-1754 (2021) Hepatology Communications |
| Popis: | 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. Marques et al. used a small chemokine‐derived positively‐charged peptide (MIG30) to neutralize the deleterious effects of extracellular DNA during drug‐induced liver injury. Treatment with MIG30 rescued mice from injury, inflammation and mortality by binding DNA avidly, dissociating it from histones and reducing the pro‐inflammatory activity of CpG DNA. |
| Databáze: | OpenAIRE |
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