RRC ID 18084
Author Loi P, Yuan Q, Torres D, Delbauve S, Laute MA, Lalmand MC, Pétein M, Goriely S, Goldman M, Flamand V.
Title Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury.
Journal Hepatology
Abstract UNLABELLED:Interferon regulatory factor 3 (IRF3) is an important transcription factor in Toll-like receptor 4 (TLR4) signaling, a pathway that is known to play a critical role in liver ischemia-reperfusion injury. In order to decipher the involvement of IRF3 in this setting, we first compared the intensity of hepatic lesions in IRF3-deficient versus wildtype mice. We found increased levels of blood transaminases, enhanced liver necrosis, and more pronounced neutrophil infiltrates in IRF3-deficient mice. Neutrophil depletion by administration of anti-Ly6G monoclonal antibody indicated that neutrophils play a dominant role in the development of severe liver necrosis in IRF3-deficient mice. Quantification of cytokine genes expression revealed increased liver expression of interleukin (IL)-12/IL-23p40, IL-23p19 messenger RNA (mRNA), and IL-17A mRNA in IRF3-deficient versus wildtype (WT) mice, whereas IL-27p28 mRNA expression was diminished in the absence of IRF3. The increased IL-17 production in IRF3-deficient mice was functionally relevant, as IL-17 neutralization prevented the enhanced hepatocellular damages and liver inflammation in these animals. Evidence for enhanced production of IL-23 and decreased accumulation of IL-27 cytokine in M1 type macrophage from IRF3-deficient mice was also observed after treatment with lipopolysaccharide, a setting in which liver gamma-delta T cells and invariant natural killer T cells were found to be involved in IL-17A hyperproduction.
CONCLUSION:IRF3-dependent events downstream of TLR4 control the IL-23/IL-17 axis in the liver and this regulatory role of IRF3 is relevant to liver ischemia-reperfusion injury.
Volume 57(1)
Pages 351-61
Published 2013-1-1
DOI 10.1002/hep.26022
PMID 22911673
MeSH Adaptor Proteins, Vesicular Transport / metabolism* Animals Female Interferon Regulatory Factor-3 / metabolism* Interleukin-17 / metabolism* Interleukins / metabolism Mice Mice, Knockout Neutrophils / physiology RNA, Messenger / metabolism Reperfusion Injury / etiology Reperfusion Injury / metabolism* Toll-Like Receptor 4 / metabolism
IF 14.679
Times Cited 24
Mice RBRC00858