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

Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage.
Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage.
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
0022-1007
1727-1737
Beraza, Naiara
8475a8e7-10f6-4dcf-a27c-2e5b28fcfda8
Malato, Yann
91f5b91b-d0da-4429-8b36-a7feecf56f86
Sander, Leif E.
10f7f5ee-58f9-4539-b96c-2d5451bdb3b4
Al-Masaoudi, Malika
d0ca2fd5-62c6-47d2-93b4-34fd7ddaf18d
Freimuth, Julia
fe3b4456-22b7-4847-b2af-2de27c1710f0
Riethmacher, Dieter
1a0a0c2e-e94d-4d0a-a890-90107a2545bc
Gores, Gregory J.
bb538d1f-5d0b-459e-9a3b-29bbaf483f0b
Roskams, Tania
e0559177-7a53-4c37-ae6f-dd3f73b1eb58
Liedtke, Christian
a072bd8a-b751-42ee-9dc3-fbba826f7047
Trautwein, Christian
8303fecc-4570-45a0-82de-2f2138b681d7
Beraza, Naiara
8475a8e7-10f6-4dcf-a27c-2e5b28fcfda8
Malato, Yann
91f5b91b-d0da-4429-8b36-a7feecf56f86
Sander, Leif E.
10f7f5ee-58f9-4539-b96c-2d5451bdb3b4
Al-Masaoudi, Malika
d0ca2fd5-62c6-47d2-93b4-34fd7ddaf18d
Freimuth, Julia
fe3b4456-22b7-4847-b2af-2de27c1710f0
Riethmacher, Dieter
1a0a0c2e-e94d-4d0a-a890-90107a2545bc
Gores, Gregory J.
bb538d1f-5d0b-459e-9a3b-29bbaf483f0b
Roskams, Tania
e0559177-7a53-4c37-ae6f-dd3f73b1eb58
Liedtke, Christian
a072bd8a-b751-42ee-9dc3-fbba826f7047
Trautwein, Christian
8303fecc-4570-45a0-82de-2f2138b681d7

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).

Record type: Article

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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Submitted date: 25 September 2008
Published date: 27 July 2009
Organisations: Human Genetics

Identifiers

Local EPrints ID: 67495
URI: https://eprints.soton.ac.uk/id/eprint/67495
ISSN: 0022-1007
PURE UUID: 6527acfc-138a-48d7-bd98-eae4bbded724
ORCID for Dieter Riethmacher: ORCID iD orcid.org/0000-0002-4206-5529

Catalogue record

Date deposited: 20 Aug 2009
Last modified: 29 Oct 2019 01:46

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Contributors

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

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