Abstract
Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage. Regulatory T cells (Tregs) are an immunosuppressive cell subset that plays an important role in a variety of liver diseases; however, data about pathological involvement of Tregs in liver steatosis of alcoholic liver disease (ALD) is insufficient. In mouse models of ALD, we found that increased lipid accumulation by chronic alcohol intake was accompanied by oxidative stress, inflammatory accumulation, and Treg decline in the liver. Adoptive transfer of Tregs relieved lipid metabolic disorder, oxidative stress, inflammation, and, consequently, ameliorated the alcoholic fatty liver. Macrophages are a dominant source of inflammation in ALD. Aberrant macrophage activation and cytokine production were activated during chronic alcohol consumption, but were significantly inhibited after Treg transfer. In vitro, macrophages were co-activated by alcohol and lipopolysaccharide to mimic a condition for alcoholic liver microenvironment. Tregs suppressed monocyte chemoattractant protein-1 and TNF-α production from these macrophages. However, such effects of Tregs were remarkably neutralized when interleukin (IL)-10 was blocked. Altogether, our data uncover a novel role of Tregs in restoring liver lipid metabolism in ALD, which partially relies on IL-10-mediated suppression of hepatic pro-inflammatory macrophages.
Highlights
Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage
We identified a reversible impact of regulatory T cell (Treg) on liver lipid metabolism in a mouse model of alcoholic fatty liver (AFL), which relies on IL-10-mediated immunosuppressive effects on pro-inflammatory macrophage activation in the hepatic microenvironment, at least in part
Adoptive transfer of Tregs protects against AFL To investigate the role of Tregs in alcoholic liver disease (ALD), Tregs were isolated from pair-fed mice and adoptively transferred to the alcohol-fed mice (Fig. 2A)
Summary
Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage. Our data uncover a novel role of Tregs in restoring liver lipid metabolism in ALD, which partially relies on IL-10-mediated suppression of hepatic pro-inflammatory macrophages.—Wang, H., T. Fatty liver had typically been considered as a benign and reversible disease, recent evidence has indicated that fat accumulation renders the liver more vulnerable to inflammatory mediators and toxic agents, leading to progression to the advanced stage of ALD [4, 5]. Elucidating the mechanism of the pathogenesis by which chronic alcohol consumption leads to excessive triglyceride (TG) accumulation and liver damage is important and may provide new insights into prevention and therapy of ALD
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