Altered Phenotype and Functionality of Circulating Immune Cells Characterize Adult Patients with Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease associated with insulin resistance and its metabolic consequences. Leukocyte mobilization, intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines contribute to the development of NASH. Though alterations in peripheral blood (PB) T cell proportions and functionality remain unidentified, they might play a main role in NASH progression. We have compared the phenotype and Th1/Th2 commitment of peripheral immune cell reservoirs in adult patients and controls as well as the ability of neutrophils and monocytes to handle an ex vivo challenge. Also, we correlated those parameters with the main histological characteristics in NASH. Compared with controls, patients showed increased numbers of CD4(+) cells and both CD4(+) and CD8(+) CD45RO subsets together with a higher frequency of IFN-γ-producing CD4(+) and CD8(+) T cells. We also found a decreased number of CD4(+) and CD8(+) CD45RA subsets. The distinctive production of IFN-γ highlights the significance of the observed skewed frequencies of PB T cells. Whereas ROS production by monocytes from NASH patients did not differ from controls, circulating neutrophils displayed a particularly higher phorbol myristate acetate-induced production of ROS. A negative correlation between oxidative burst and fibrosis grade was observed. This study reveals the presence of a characteristic profile of peripheral immune cells in NASH. We also discuss the probable influence of obesity on some of our present findings.

Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver

“…+ and CD8 + cells in the peripheral blood; no change was observed for IL-4 + CD4 + cells (21). Further data on the impact of intrahepatic Th1 and Th2 effector T cells in NASH are derived from mouse experiments in various models of NASH.…”

The role of neutrophils in the development of liver diseases

“…28 Additionally, dietary reversion suppressed uncoupling protein 2 expression and increased hepatic ATP levels, conditions that might favor apoptosis rather than reactive oxygen speciesmediated hepatocyte necrosis. 29 Neutrophil dysfunction was also associated with liver fibrosis and cirrhosis in NASH. Indeed, human neutrophil peptides have the ability to enhance hepatic fibrosis in fatty liver diseases by inducing hepatic stellate cell proliferation.…”

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…In addition, cytokines are not only being produced by local sources but also by peripheral blood cells. The presence of an altered phenotype and functionality of circulating immune cells has been speculated to be a distinctive characteristic in NASH patients [76,77] . Innate immune cells have the ability to secrete cyto-kines and to promote influx of inflammatory cells.…”

“…Innate immune cells have the ability to secrete cyto-kines and to promote influx of inflammatory cells. To date, emerging strong evidences suggested that cytokines such as TNF-α and IL-1 are sensitising factors acting upon leukocyte infiltration of the liver [76,78] . These cytokines and chemokines effects contributed to intracellular oxidative stress and mitochondrial dysfunction, which amplified hepatocytes damage.…”

“…The cytokines mechanism appears to be like a vicious cycle. The further disrupted cellular mitochondrial respiratory chain can thereby cause the formation reactive oxidative species of nearby hepatocytes [76] . As a consequence, HSCs is activated and lead to hepatic fibrosis.…”