Browsing by Author "Ju, Cynthia"

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    IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages
    (Elsevier, 2017) Wang, Meng; Shen, Guannan; Xu, Liangguo; Liu, Xiaodong; Brown, Jared M.; Feng, Dechun; Ross, Ruth Ann; Gao, Bin; Liangpunsakul, Suthat; Ju, Cynthia; Medicine, School of Medicine
    Background & Aim Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-κB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-κB activation. The role of IL-33/ST2 in ALD has not been studied. Methods Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild-type, IL-33−/− and ST2−/− mice in several models. Results Elevation of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2-deletion exacerbated ALD, through enhancing NF-κB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33−/− and ST2−/− mice compared to wild-type mice. Conclusion Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-κB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL-33/ST2 signaling and exacerbates tissue damage. Lay summary In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages.
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    Role of hepatic macrophages in alcoholic liver disease
    (BMJ Journals, 2016-08) Ju, Cynthia; Liangpunsakul, Suthat; Medicine, School of Medicine
    Alcohol consumption can lead to the increase in gut permeability and cause the translocation of bacteria-derived lipopolysaccharides from the gut to the liver, which subsequently activates immune responses. In this process, macrophages play a critical role and involve in the pathogenesis of alcoholic liver disease (ALD). To define the mechanism underpinning the function of macrophages, it is important to conduct extensive studies to further explicate the phenotypic diversity of macrophages in the context of ALD., In this review, the role of hepatic macrophages in the pathogenesis of ALD is discussed.