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

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Title: Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury
Authors: Loi, Patrizia, Yuan, qing, Torres, David, Delbauve, Sandrine, Laute, Marie-Aline, Lalmand, Marie-Claude, Petein, Michel, Goriely, Stanislas, Goldman, Michel, Flamand, Véronique
Source: Hepatology. 57:351-361
Publisher Information: Ovid Technologies (Wolters Kluwer Health), 2013.
Publication Year: 2013
Subject Terms: 0301 basic medicine, Interleukin-17 -- metabolism, Neutrophils, Knockout, Neutrophils -- physiology, Interleukins -- metabolism, Mice, 03 medical and health sciences, Immunologie, Toll-Like Receptor 4 -- metabolism, Animals, RNA, Messenger, Mice, Knockout, 0303 health sciences, Interleukins, Interleukin-17, Adaptor Proteins, 3. Good health, Messenger -- metabolism, Toll-Like Receptor 4, Adaptor Proteins, Vesicular Transport, Vesicular Transport -- metabolism, Interferon Regulatory Factor-3 -- metabolism, Reperfusion Injury, RNA, Female, Interferon Regulatory Factor-3, Reperfusion Injury -- etiology -- metabolism
Description: Abstract 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)
Document Type: Article
File Description: 1 full-text file(s): application/pdf
Language: English
ISSN: 0270-9139
DOI: 10.1002/hep.26022
Access URL: https://aasldpubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hep.26022
https://pubmed.ncbi.nlm.nih.gov/22911673
https://onlinelibrary.wiley.com/doi/10.1002/hep.26022/pdf
https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.26022
https://difusion.ulb.ac.be/vufind/Record/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/145611/Details
http://onlinelibrary.wiley.com/doi/10.1002/hep.26022/abstract
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.26022
https://www.ncbi.nlm.nih.gov/pubmed/22911673
Rights: Wiley TDM
Accession Number: edsair.doi.dedup.....21404565dac54ae19d9bfdd0b90677f4
Database: OpenAIRE
Description
Abstract:Abstract 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)
ISSN:02709139
DOI:10.1002/hep.26022