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 and Trautwein, Christian (2009) Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. The Journal of Experimental Medicine, 206 (8), 1727-1737. (doi:10.1084/jem.20082152).

Abstract

Nuclear factor ?B (NF-?B) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-B activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMO?hepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMO?hepa 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?hepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMO?hepa 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 NEMO?hepa 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, NEMO?hepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies

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Contributors

Author: Dieter Riethmacher

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