Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage.
Nuclear factor kappaB (NF-kappaB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-kappaB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMO(Delta hepa)) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMO(Delta 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(Delta hepa) livers. Interestingly, depletion of the NK1.1(+) cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMO(Delta 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(Delta 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(Delta hepa) mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.
Beraza
Naiara
N
Department of Internal Medicine III, University Hospital (RWTH) Aachen, Aachen 5205, Germany.
Malato
Yann
Y
Sander
Leif E
LE
Al-Masaoudi
Malika
M
Freimuth
Julia
J
Riethmacher
Dieter
D
Gores
Gregory J
GJ
Roskams
Tania
T
Liedtke
Christian
C
Trautwein
Christian
C
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000276:immunology / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D019014:fas Receptor