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TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.

Fernández-Álvarez S, Gutiérrez-de Juan V, Zubiete-Franco I, Barbier-Torres L, Lahoz A, Parés A, Luka Z, Wagner C, Lu SC, Mato JM, Martínez-Chantar ML, Beraza N - Lab. Invest. (2014)

Bottom Line: Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis.The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis.Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.

ABSTRACT
Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Cirrhotic patients show low expression of GNMT that is absent in hepatocellular carcinoma (HCC) samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis, and HCC. Lack of GNMT triggers NK cell activation in GNMT(-/-) mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL(-/-)/GNMT(-/-) mice in which we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT(-/-) and TRAIL(-/-)/GNMT(-/-) mice. In GNMT(-/-) mice, exacerbated fibrogenic response after BDL concurred with NK1.1(+) cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT(-/-) mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL(-/-)/GNMT(-/-) mice showed significantly less fibrosis after BDL than GNMT(-/-) mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT(-/-) mice. Finally, in vivo silencing of DR5 efficiently protected GNMT(-/-) mice from BDL-liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.

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Low GNMT expression in human PBC livers(A) IHC and (B) further quantification using FRIDA software showing lower GNMT expression in human samples from PBC patients at initial stages or after transplantation compared to healthy controls. n= 8–10. **p< 0.01 (Healthy vs early PBC and healthy vs late PBC). Error bars represent SD.
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Figure 1: Low GNMT expression in human PBC livers(A) IHC and (B) further quantification using FRIDA software showing lower GNMT expression in human samples from PBC patients at initial stages or after transplantation compared to healthy controls. n= 8–10. **p< 0.01 (Healthy vs early PBC and healthy vs late PBC). Error bars represent SD.

Mentions: Previous work showed that glycine-N-methyltransferase (GNMT) expression is significantly downregulated in cirrhotic patients from alcohol and HCV etiologies2. Here we show that expression of GNMT was also decreased in the context of chronic cholestatic liver disease. Thus, livers from patients with primary biliary cirrhosis (PBC), both at initial stages and in patients with advanced disease that were transplanted, had significantly lower levels of GNMT than healthy livers as shown by IHC and further quantification (Fig. 1A, B). The finding that attenuation of GNMT was found at early stages of cholestatic liver disease, where fibrosis is not prominent, points to GNMT deficiency as a contributor/mediator of fibrogenesis rather than a consequence.


TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.

Fernández-Álvarez S, Gutiérrez-de Juan V, Zubiete-Franco I, Barbier-Torres L, Lahoz A, Parés A, Luka Z, Wagner C, Lu SC, Mato JM, Martínez-Chantar ML, Beraza N - Lab. Invest. (2014)

Low GNMT expression in human PBC livers(A) IHC and (B) further quantification using FRIDA software showing lower GNMT expression in human samples from PBC patients at initial stages or after transplantation compared to healthy controls. n= 8–10. **p< 0.01 (Healthy vs early PBC and healthy vs late PBC). Error bars represent SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4310762&req=5

Figure 1: Low GNMT expression in human PBC livers(A) IHC and (B) further quantification using FRIDA software showing lower GNMT expression in human samples from PBC patients at initial stages or after transplantation compared to healthy controls. n= 8–10. **p< 0.01 (Healthy vs early PBC and healthy vs late PBC). Error bars represent SD.
Mentions: Previous work showed that glycine-N-methyltransferase (GNMT) expression is significantly downregulated in cirrhotic patients from alcohol and HCV etiologies2. Here we show that expression of GNMT was also decreased in the context of chronic cholestatic liver disease. Thus, livers from patients with primary biliary cirrhosis (PBC), both at initial stages and in patients with advanced disease that were transplanted, had significantly lower levels of GNMT than healthy livers as shown by IHC and further quantification (Fig. 1A, B). The finding that attenuation of GNMT was found at early stages of cholestatic liver disease, where fibrosis is not prominent, points to GNMT deficiency as a contributor/mediator of fibrogenesis rather than a consequence.

Bottom Line: Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis.The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis.Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.

ABSTRACT
Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Cirrhotic patients show low expression of GNMT that is absent in hepatocellular carcinoma (HCC) samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis, and HCC. Lack of GNMT triggers NK cell activation in GNMT(-/-) mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL(-/-)/GNMT(-/-) mice in which we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT(-/-) and TRAIL(-/-)/GNMT(-/-) mice. In GNMT(-/-) mice, exacerbated fibrogenic response after BDL concurred with NK1.1(+) cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT(-/-) mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL(-/-)/GNMT(-/-) mice showed significantly less fibrosis after BDL than GNMT(-/-) mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT(-/-) mice. Finally, in vivo silencing of DR5 efficiently protected GNMT(-/-) mice from BDL-liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.

Show MeSH
Related in: MedlinePlus