Liver Immune Cells Release Type 1 Interferon Due to DNA Sensing and Amplify Liver Injury from Acetaminophen Overdose

作者：Alan de Araujo, Maísa Mota Antunes, Matheus Silvério Mattos, Ariane Barros Diniz, Débora Moreira Alvarenga, Brenda Naemi Nakagaki, Érika de Carvalho, Viviane Aparecida Souza Lacerda, Raquel Carvalho-Gontijo, Jorge Luiz de Jesus Goulart, Kassiana Mafra, Maria Alice Freitas‐Lopes, Hortência Maciel de Castro Oliveira, Camila Miranda Dutra, Bruna Araújo David, Aristóbolo M. Silva, Valérie Quesniaux, Bernhard Ryffel, Sérgio C. Oliveira, Glen N. Barber, Daniel Santos Mansur, Thiago M. Cunha, Rafael M. Rezende, A. G. de Oliveira, Gustavo Batista Menezes · 发表于：Cells · 年份：2018 · DOI：10.3390/cells7080088 · 被引用次数：39 · 研究领域：interferon and immune responses、Hepatitis C virus research、Liver Disease Diagnosis and Treatment

Hepatocytes may rupture after a drug overdose, and their intracellular contents act as damage-associated molecular patterns (DAMPs) that lead to additional leukocyte infiltration, amplifying the original injury. Necrosis-derived DNA can be recognized as a DAMP, activating liver non-parenchymal cells (NPCs). We hypothesized that NPCs react to DNA by releasing interferon (IFN)-1, which amplifies acetaminophen (APAP)-triggered liver necrosis. We orally overdosed different knockout mouse strains to investigate the pathways involved in DNA-mediated amplification of APAP-induced necrosis. Mice were imaged under intravital confocal microscopy to estimate injury progression, and hepatocytes and liver NPCs were differentially isolated for gene expression assays. Flow cytometry (FACS) using a fluorescent reporter mouse estimated the interferon-beta production by liver leukocytes under different injury conditions. We also treated mice with DNase to investigate the role of necrosis DNA signaling in IFN-1 production. Hepatocytes released a large amount of DNA after APAP overdose, which was not primarily sensed by these cells. However, liver NPCs promptly sensed such environmental disturbances and activated several DNA sensing pathways. Liver NPCs synthesized and released IFN-1, which was associated with concomitant hepatocyte necrosis. Ablation of IFN-1 recognition in interferon α/β receptor (IFNAR−/−) mice delayed APAP-mediated liver necrosis and dampened IFN-1 sensing pathways. We demon...