Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Hepatology Année : 2015

Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice

Mauro Martins Teixeira
  • Fonction : Auteur
  • PersonId : 965958

Résumé

Drug-induced liver injury (DILI) is an important cause of acute liver failure with limited therapeutic options. During DILI, oncotic necrosis with concomitant release and recognition of intracellular content amplifies liver inflammation and injury. Amongst these molecules, self-DNA has been widely shown to trigger inflammatory and autoimmune diseases; however, whether DNA released from damaged hepatocytes accumulates into necrotic liver and the impact of its recognition by the immune system remains elusive. Here we showed that treatment with two different hepatotoxic compounds (acetaminophen and thioacetamide) caused DNA release into the hepatocyte cytoplasm, which occurred in parallel with cell death in vitro. Administration of these compounds in vivo caused massive DNA deposition within liver necrotic areas, together with an intravascular DNA coating. Using confocal intravital microscopy, we revealed that liver injury due to acetaminophen overdose led to a directional migration of neutrophils to DNA-rich areas, where they exhibit an active patrolling behavior. DNA removal by intravenous DNASE1 injection or ablation of TLR9-mediated sensing significantly reduced systemic inflammation, liver neutrophil recruitment and hepatotoxicity. Analysis of liver leukocytes by flow cytometry revealed that emigrated neutrophils upregulated TLR9 expression during acetaminophen-mediated necrosis, and these cells sensed and reacted to extracellular DNA by activating the TLR9/NF-κB pathway. Likewise, adoptive transfer of wild-type neutrophils to TLR9(-/-) mice reversed the hepatoprotective phenotype otherwise observed in TLR9 absence. Conclusion: We described that hepatic DNA accumulation is a novel feature of DILI pathogenesis and blockage of DNA recognition by the innate immune system may consist in a promising therapeutic venue.

Mots clés

Domaines

Biologie animale

Dates et versions

hal-01145643 , version 1 (24-04-2015)

Identifiants

Citer

Pedro Elias Marques, André Gustavo Oliveira, Rafaela Vaz Pereira, Bruna Araújo David, Lindisley Ferreira Gomides, et al.. Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice. Hepatology, 2015, 61 (1), pp.348-360. ⟨10.1002/hep.27216⟩. ⟨hal-01145643⟩
181 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More