Abstract
Non-alcoholic fatty liver disease (NAFLD), and the progressive stage non-alcoholic steatohepatitis (NASH), is the predominant cause of chronic liver disease globally. As part of the complex pathogenesis, natural killer (NK) cells have been implicated in the development of liver inflammation in experimental murine models of NASH. However, there is a lack of knowledge on how NK cells are affected in humans with this disease. Here, we explored the presence of disease-specific changes within circulating and tissue-resident NK cell populations, as well as within other major immune cell subsets, in patients with liver biopsy-confirmed NAFLD. Using 18-color-flow cytometry, substantial changes were observed in certain myeloid populations in patients as compared to controls. NK cell numbers, on the other hand, were not altered. Furthermore, only minor differences in expression of activating and inhibitory NK cell receptors were noted, with the exception of an increased expression of NKG2D on NK cells from patients with NASH. NK cell differentiation remained constant, and NK cells from these patients retain their ability to respond adequately upon stimulation. Instead, considerable alterations were observed between liver, adipose tissue, and peripheral blood NK cells, independently of disease status. Taken together, these results increase our understanding of the importance of the local microenvironment in shaping the NK cell compartment and stress the need for further studies exploring how NASH affects intrahepatic NK cells in humans.
Highlights
natural killer (NK) cells are an important part of innate immunity where they participate in the defense against viral infections and in tumor surveillance [1] Upon activation, NK cells perform cytotoxicity by the release of cytolytic granules
Few differences were noted among CD4, CD8, and γδ T cells, a trend toward a decline in mucosa-associated T (MAIT) cells was observed in non-alcoholic steatohepatitis (NASH) patients as compared to nonalcoholic fatty liver (NAFL) patients and healthy controls (Figure 1B)
Alterations could be observed in certain innate immune cell subsets, the overall size of the peripheral blood NK cell compartment remained unaltered in NAFL and NASH
Summary
NK cells are an important part of innate immunity where they participate in the defense against viral infections and in tumor surveillance [1] Upon activation, NK cells perform cytotoxicity by the release of cytolytic granules. This view has been revised in the last decade and it is clear that NK cells gradually undergo directed differentiation even after they have reached the CD56dim stage [2] In addition to their presence in the circulation, NK cells are found in numerous peripheral tissues and are especially enriched in the liver and uterus where they comprise up to 30 and 45%, respectively, of all lymphocytes [3, 4]. The role of NK cells in many other liver diseases remains elusive
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