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


ABSTRACT: 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 ?/? receptor (IFNAR-/-) mice delayed APAP-mediated liver necrosis and dampened IFN-1 sensing pathways. We demonstrated a novel loop involving DNA recognition by hepatic NPCs and additional IFN-1 mediated hepatocyte death.

SUBMITTER: Araujo AM 

PROVIDER: S-EPMC6115735 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Araujo Alan Moreira de AM   Antunes Maísa Mota MM   Mattos Matheus Silvério MS   Diniz Ariane Barros AB   Alvarenga Débora Moreira DM   Nakagaki Brenda Naemi BN   Carvalho Érika de É   Lacerda Viviane Aparecida Souza VAS   Carvalho-Gontijo Raquel R   Goulart Jorge J   Mafra Kassiana K   Freitas-Lopes Maria Alice MA   Oliveira Hortência Maciel de Castro HMC   Dutra Camila Miranda CM   David Bruna Araújo BA   Mendes Silva Aristóbolo A   Quesniaux Valerie V   Ryffel Bernhard B   Oliveira Sergio Costa SC   Barber Glen N GN   Mansur Daniel Santos DS   Cunha Thiago Mattar TM   Rezende Rafael Machado RM   Oliveira André Gustavo AG   Menezes Gustavo Batista GB  

Cells 20180727 8


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  ...[more]

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