Interferon regulatory factor 3 deficiency leads to interleukin‐17‐mediated liver ischemia‐reperfusion injury

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. (HEPATOLOGY 2013)