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Conditional deletion of biliverdin reductase in macrophages determines the sensitivity to acetaminophen injury.
Author(s) -
Wegiel Barbara,
Gallo David,
Csizmadia Eva,
Nemeth Zsuzsanna,
Kelly Vincent,
Mantle Tim,
Alam Jawed
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb794
Subject(s) - biliverdin reductase , tlr9 , in vivo , liver injury , conditional gene knockout , in vitro , lipopolysaccharide , microbiology and biotechnology , chemistry , acetaminophen , biliverdin , pharmacology , biology , immunology , biochemistry , heme oxygenase , heme , enzyme , gene , gene expression , genetics , phenotype , dna methylation
Biliverdin reductase (BVR) is a multifunctional enzyme, kinase, receptor as well as exhibiting transcription factor activity. We have recently elucidated mechanisms by which BV and BVR regulate the innate inflammatory response in vitro and in vivo. In this study we aimed to elucidate the role of BVR in vivo in response acetaminophen‐mediated liver injury using newly generated BVR conditional knockout mice. We confirmed lack of BVR in the Cre‐Lyz‐BVR‐fl/fl macrophages in vivo as well as in bone‐marrow derived macrophgaes. We validated decreased bilirubin levels in BVR deficient mice. Importantly after challenge with LPS+D‐Gal Cre‐Lyz‐BVR‐fl/fl mice show greater injury as compare to BVR‐fl/fl control mice. However, Cre‐Lyz‐BVR‐fl/fl mice were resistant to acetaminophen induced liver injury. Lack of BVR in macrophages led to low inflammatory responses to TLR9 ligands (CpG rich region) in vitro and in vivo. We showed that BVR binds specific DNA sequences in the membrane and may be a novel mediator of TLR9 signaling. In summary, BVR in macrophages is critical for acetaminophen mediated liver injury due to its interaction with DNA released from necrotic cells and amplification of inflammation.