Date: Monday, June 3, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: The current study was undertaken to assess the role of inflammatory signaling during induction of and recovery from acetaminophen induced acute liver failure.
*Methods: C57BL/6 wild type male mice and mice deficient in TRIF (an adapter protein required for TLR4 signal transduction) or interferon response (IFNAR1, IFIT1, IFIT2) on C57Bl/6 background were injected i.p. with APAP (300mg/kg body weight). Serum AST/ALT was measured in blood collected from the inferior vena cava. Liver tissues were collected for histological and biochemical studies after perfusion. Cell proliferation was measured by immunohistochemistry in tissue from mice injected with BrDU, 16 hours before sacrifice. Non parenchymal (NPC) cells, particularly CD11b+ cells were purified from the liver by magnetic bead separation. Gene expression (mRNA and protein) was measured using qRT-PCR and Western blotting. The role of individual cell components was evaluated by using conditional gene targeting.
*Results: TRIF-/- mice exhibit prolongation of hepatocyte injury reflected by elevated serum AST/ALT levels, duration of hepatocyte necrosis, and delayed hepatocyte proliferation. Comparable outcomes were obtained in mice deficient in transcription factor IRF3, the type I IFN receptor (IFNAR1) and the interferon inducible gene family IFIT1-2. Sensitivity to type I IFN and production of IFN-induced IFIT2 was shown to be limited to myeloid cells using mice with cell type specific deficiency in IFNAR1 or IFIT2 targeted to either hepatocytes using Alb-cre or myeloid cells using LysM-cre.
*Conclusions: APAP induced acute liver injury results in rapid liver necrosis and infiltration of inflammatory CD11b+/LY6C+ monocytes. TLR signaling through the TRIF pathway, IRF3-dependent type I IFN production, and response to IFN in myeloid cells enables more rapid tissue repair leading to enhanced hepatocyte proliferation.
To cite this abstract in AMA style:Datta S, Hamilton T, Sen GC. Interferon Sensitivity Promotes Recovery from Acetaminophen Induced Liver Injury [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/interferon-sensitivity-promotes-recovery-from-acetaminophen-induced-liver-injury/. Accessed October 23, 2020.
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