Journal of Liver

Hepatic DNA deposition drives drug-induced liver injury and inflammation

World Congress on Hepatitis

July 20-22, 2015 Orlando, Florida, USA

Pedro Elias Marques

Posters-Accepted Abstracts: J Liver

Abstract:

Drug-induced liver injury (DILI) is an important medical problem worldwide, but with limited therapeutic options. During DILI, hepatic necrosis with concomitant release of intracellular content induces liver inflammation and injury. Amongst these intracellular molecules, DNA has been widely shown to trigger inflammatory and autoimmune diseases. However, the mechanisms involved in DNA release and accumulation into the necrotic liver, and the impact of its recognition by the immune system remains elusive. Here we showed that treatment with different hepatotoxic compounds (acetaminophen and thioacetamide) caused DNA release to the hepatocyte cytoplasm, which occurred in parallel with cell death in vitro. Administration of these toxins in vivo caused massive DNA deposition within liver necrotic areas, together with a widespread intravascular DNA coating. Using confocal intravital microscopy, we showed that liver injury led to a directional migration of neutrophils to DNA-rich areas, where they exhibited an active patrolling behavior. Interestingly, DNA deposits were negative for neutrophil elastase, suggesting it was not derived from neutrophil extracellular traps. DNA removal by intravenous DNASE1 injection or blockage of TLR9-mediated sensing significantly reduced systemic inflammation, liver neutrophil recruitment and hepatotoxicity. Flow cytometry of liver leukocytes revealed that emigrated neutrophils upregulated TLR9 expression in the plasma membrane during liver necrosis, and these cells sensed and reacted to extracellular DNA by up-regulating NF-?B and CXCR2 expression. Likewise, adoptive transfer of wild-type neutrophils to TLR9-/- mice reversed the hepatoprotective phenotype otherwise observed in TLR9 absence. We concluded 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 for DILI.