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Cells. 2018 Jul 27;7(8). pii: E88. doi: 10.3390/cells7080088.

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

Author information

1
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. amoreiradearaujo@gmail.com.
2
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. maisaantunes@gmail.com.
3
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. mattosms@yahoo.com.br.
4
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. abarrosdiniz@gmail.com.
5
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. deboraalvarenga@yahoo.com.
6
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. brendanaemi22@gmail.com.
7
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. erikacarvalhobio@gmail.com.
8
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. viviane_lacerda@outlook.com.
9
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. rakel.cg@gmail.com.
10
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. jorge.ferreira@cpqrr.fiocruz.br.
11
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. kassiana93@gmail.com.
12
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. licefl95@gmail.com.
13
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. hortsmaciel@gmail.com.
14
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. camiladutra_mm@hotmail.com.
15
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. brunaraujodavid@gmail.com.
16
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil. aristobolosilva@gmail.com.
17
Experimental and Molecular Immunology and Neurogenetics CNRS, University of Orleans, 45000 Orleans, France. quesniaux@cnrs-orleans.fr.
18
Experimental and Molecular Immunology and Neurogenetics CNRS, University of Orleans, 45000 Orleans, France. bernhard.ryffel@cnrs-orleans.fr.
19
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil. scozeus1@gmail.com.
20
Department of Cell Biology and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. gbarber@med.miami.edu.
21
Laboratory of Immunobiology, Universidade Federal de Santa Catarina, Santa Catarina 88040-900, Brazil. mansurds@gmail.com.
22
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo 14049-900, Brazil. thicunha@usp.br.
23
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. rmachadorezende@bwh.harvard.edu.
24
Departamento de Fisiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil. agoufmg@gmail.com.
25
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Belo Horizonte, Minas Gerais 31270-901, Brazil. menezesgb@ufmg.br.

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 α/β 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.

KEYWORDS:

DNA sensing; hepatology; immune system; immunity; in vivo imaging

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