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.


CONCLUSIONS
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.
Institut d'Immunologie Médicale, Université Libre de Bruxelles, Gosselies, Belgium.
Patrizia
P
Loi
Qing
Q
Yuan
David
D
Torres
Sandrine
S
Delbauve
Marie-Aline
MA
Laute
Marie-Claude
MC
Lalmand
Michel
M
Pétein
Stanislas
S
Goriely
Michel
M
Goldman
Véronique
V
Flamand
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D005260:Female; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D020381:Interleukin-17; D007378:Interleukins; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; C098680:Il17a protein, mouse; C494233:Irf3 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse