Hepatic DNA deposition drives drug‐induced liver injury and inflammation in mice. Issue 1 (31st July 2014)

• Record Type: Journal Article
• Authors: Marques, Pedro Elias; Oliveira, André Gustavo; Pereira, Rafaela Vaz; David, Bruna Araújo; Gomides, Lindisley Ferreira; Saraiva, Adriana Machado; Pires, Daniele Araújo; Novaes, Júlia Tosta; Patricio, Daniel O.; Cisalpino, Daniel; Menezes‐Garcia, Zélia; Leevy, W. Matthew; Chapman, Sarah Ellen; Mahecha, GermánArturo; Marques, Rafael Elias; Guabiraba, Rodrigo; Martins, Vicente Paulo; Souza, Danielle Gloria; Mansur, Daniel Santos; Teixeira, Mauro Martins; Leite, M. Fatima; Menezes, Gustavo Batista
• Is Part Of: Hepatology. Volume 61:Issue 1(2015:Jan.)
• Page Start: 348
• Page End: 360
• Publication Date: 2014-07-31
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27216
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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. Among 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 show that treatment with two different hepatotoxic compounds (acetaminophen and thioacetamide) caused DNA release into the hepatocyte cytoplasm, which occurred in parallel with cell death <italic>in vitro</italic>. Administration of these compounds <italic>in vivo</italic> 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 Toll‐like receptor 9 (TLR9)‐mediated sensing significantly reduced systemic inflammation, liver neutrophil recruitment, and hepatotoxicity. Analysis of liver leukocytes by flow cytometry revealed that emigrated neutrophils up‐regulated 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<sup>−/−</sup> mice reversed the hepatoprotective phenotype otherwise observed in TLR9 absence. <italic>Conclusion</italic>: Hepatic DNA accumulation is a novel feature of DILI pathogenesis. Blockage of DNA recognition by the innate immune system may constitute a promising therapeutic venue. (H<sc>epatology</sc> 2015;61:348–360)</p> </abstract>