Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage

Naiara Beraza, Yann Malato, Leif E. Sander, Malika Al-Masaoudi, Julia Freimuth, Dieter Riethmacher, Gregory J. Gores, Tania Roskams, Christian Liedtke, Christian Trautwein

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Abstract

Nuclear factor κB (NF-κB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-κB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMO Δhepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMOΔhepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMO Δhepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMOΔhepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)-mediated injury. The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient -/- mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.

Original languageEnglish
Pages (from-to)1727-1737
Number of pages11
JournalJournal of Experimental Medicine
Volume206
Issue number8
DOIs
Publication statusPublished - Aug 3 2009
Externally publishedYes

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Natural Killer T-Cells
Natural Killer Cells
Hepatocytes
Liver
Apoptosis
Concanavalin A
Inflammation
Liver Diseases
Adoptive Transfer
Liver Neoplasms
Hepatitis
Disease Progression
Hepatocellular Carcinoma
Histology
Chronic Disease
Transcription Factors
Up-Regulation
Tumor Necrosis Factor-alpha
Ligands
Wounds and Injuries

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Beraza, N., Malato, Y., Sander, L. E., Al-Masaoudi, M., Freimuth, J., Riethmacher, D., ... Trautwein, C. (2009). Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. Journal of Experimental Medicine, 206(8), 1727-1737. https://doi.org/10.1084/jem.20082152

Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. / Beraza, Naiara; Malato, Yann; Sander, Leif E.; Al-Masaoudi, Malika; Freimuth, Julia; Riethmacher, Dieter; Gores, Gregory J.; Roskams, Tania; Liedtke, Christian; Trautwein, Christian.

In: Journal of Experimental Medicine, Vol. 206, No. 8, 03.08.2009, p. 1727-1737.

Research output: Contribution to journalArticle

Beraza, N, Malato, Y, Sander, LE, Al-Masaoudi, M, Freimuth, J, Riethmacher, D, Gores, GJ, Roskams, T, Liedtke, C & Trautwein, C 2009, 'Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage', Journal of Experimental Medicine, vol. 206, no. 8, pp. 1727-1737. https://doi.org/10.1084/jem.20082152
Beraza, Naiara ; Malato, Yann ; Sander, Leif E. ; Al-Masaoudi, Malika ; Freimuth, Julia ; Riethmacher, Dieter ; Gores, Gregory J. ; Roskams, Tania ; Liedtke, Christian ; Trautwein, Christian. / Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 8. pp. 1727-1737.
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