Discovered that 'Killer Cells” Contribute to Hepatitis

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A team of CIC bioGUNE researchers, led by Dr. Naiara Beraza, have discovered that 'natural killer' (NK) cells are fundamental in the inflammation of the liver during the early stages of non-alcoholic steatohepatitis (NASH).

The research was published recently in Hepatology wherein the therapeutic potential of the inactivation of these NK cells and the inhibition of the expression of TRAILs (TNF-related apoptosis-inducing ligands) was highlighted, the aim being to halt the progress of the NASH.

Obesity, currently considered to be an epidemic in Western countries, is closely linked to steatosis (the accumulation of fat in the liver), which is considered a benign condition in patients and may become chronic for the rest of one's life. Nevertheless, steatosis may turn into steatohepatitis, the chronic inflammation of the liver. This condition has very harmful consequences for the liver and is deemed a point of no return in the development of non-alcoholic steatohepatitis (NASH).

The inflammation may give rise to fibrogenesis, cirrhosis and, finally, to hepatocellular carcinoma (HCC), which is the third cause of death amongst patients with cancer. As a consequence, it is of vital importance to identify the molecular mechanisms that cause chronic inflammation within the development of NASH, and find new molecular targets for the early diagnosis and treatment of the illness.

The research team, led by Dr. Naiara Beraza, undertook their work in the laboratory of CIC bioGUNE's Metabolomic Unit - directed by Dr. Maria Luz Martínez Chantar -, which demonstrated the role of the "natural killer" or NK cells as principal inductors of the inflammation in the early stages of NASH. Moreover, they showed that the TRAILs have a notable influence on this prejudicial role of the NK cells.

This research has been published in the Hepatology journal and reveals a new mechanism according to which the TRAIL-producing NK cells foment inflammation in the steatotic livers of mice deficient in the glycine-N-methyltransferase enzyme (GNMT). The S-adenosylmethionine (SAMe) is the principal donor of methyl groups of the organism, and GNMT is the enzyme that catabolises it. It is significant that patients with cirrhosis have a low expression of GNMT, the presence of which is non-existent in HCC.

"TRAIL is a therapeutic tool recognised for the treatment of various types of tumours in patients, given that this cytokine, produced by NK cells, only destroys those cells transformed or infected by virus. Nevertheless, our research highlights the harmful effect of the activation of NK cells and of the production of TRAIL in steatotic livers, as this promotes cell death amongst hepatocytes which gives rise to chronic inflammation - the pathogenic condition that precedes cirrhosis and the onset of HCC", stated Dr. Beraza.

"Moreover, the research shows that the GNMT-deficient hepatocytes, which accumulate lipids, actively express NK cell ligands, and result in these hepatocytes being classed as damaged or transformed and, thus, lead to their death through mechanisms involving TRAILs", concluded Dr Beraza.

A complex process

The pathogenesis of NASH is a complex process involving a number of cell activities such as the accumulation of lipids, apoptosis, inflammation, fibrogenesis and tumorigenesis, amongst others. An important part of this pathogenesis of NASH involves abnormal bacterian proliferation and the permeabilisation of the intestine, thus exposing the liver to a greater amount of endotoxin.

"The macrophages are usually described as the principal cell component capable of countering liver damage caused by endotoxins", pointed out Dr. Beraza. "Curiously, we have found that the deficiency in GNMT makes the liver more sensitive to damage caused by endotoxins, and that this damage is due to the NK cells that express TRAILs, while it would appear that the role of the macrophages in the process turns out to be less relevant. In this way we have shown that the inactivation of the NK cells and/or the absence of TRAILs protect the liver against bacterial infections at the early stages of hepatic steatosis".

To sum up, the work of the research team led by Dr. Beraza defines the fundamental role of the TRAIL-producing NK cells during the progress of liver damage in the absence of GNMT, and points to this cell behaviour as the possible mediator in the chronic disease at the onset of NASH. Moreover, the results highlight the therapeutic potential of the early detection of activation of NK cells and the subsequent blocking of TRAIL production, and the activity of these immunological cells in order to counter hepatic inflammation during steatosis. "Our research provides new evidence on the importance of the innate immune system in the biology of the liver and on the fundamental role of the NK cells in the pathogenesis of NASH", concluded Dr. Beraza.

Bibliographic references of the study:

Inhibition of NK cells protects the liver against acute injury in the absence of GNMT.
Gomez-Santos L, Luka Z, Wagner C, Fernandez-Alvarez S, Lu SC, Mato JM, Martinez-Chantar ML and Beraza N. Hepatology. 5 March 2012 [electronic publication prior to printing].

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