Immunity and inflammatory signaling in alcoholic liver disease

Mandrekar, Pranoti; Ambade, Aditya

doi:10.1007/s12072-014-9518-8

Cited by 14 publications

(10 citation statements)

References 53 publications

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“…Chronic hepatic injury caused by alcohol abuse was found mediated by the immune response in which both proinflammatory and anti-inflammatory leukocyte lineages were involved. 35,36 We first established the profile of the associated immune cells in mice with alcohol exposure ( Figure S3). The immunosuppressive function of gated CD11b + Ly6G high Ly6C int cells was demonstrated in our previous paper, 15 which could support the definition of this population as G-MDSC-like cells.…”

Section: Berberine Induced G-mdsc-like Cells Expansion In Niaaa Micementioning

confidence: 99%

Modulation of gut microbiota mediates berberine‐induced expansion of immuno‐suppressive cells to against alcoholic liver disease

Wang

Tan

et al. 2020

Clinical & Translational Med

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Background Berberine is an isoquinoline alkaloid compound derived from many herbs, which has been used extensively to improve liver function. But action mechanism of its hepatoprotection in alcoholic liver disease (ALD) is far from being clear. Aim To investigate the underlying mechanism of berberine's therapeutic effect on ALD associated with gut microbiota‐immune system axis. Method An animal model fed with ethanol that mimics drinking pattern ideally in ALD patients was established. Liver function was evaluated by biochemical test and histological examination. Immune cells were detected by flow cytometry and feces samples were collected for 16S rRNA gene amplicon sequencing. Results We first reported the promising beneficial effect of berberine on ameliorating acute‐on‐chronic alcoholic hepatic damage and explored the underlying mechanism involving gut microbiota‐immune system axis. Notably, berberine activated a population with immune suppressive function, defined as granulocytic‐ myeloid‐derived suppressor cell (G‐MDSC)‐like population, in the liver of mice with alleviating alcohol‐induced hepatic injury. Berberine remarkably enhanced the increase of G‐MDSC‐like cells in blood and liver and decreased cytotoxic T cells correspondingly. Suppression of G‐MDSC‐like population significantly attenuated the protective effect of berberine against alcohol. Berberine activated IL6/STAT3 signaling in in vitro culture of G‐MSDCs‐like population, while inhibition of STAT3 activity attenuated the activation of this population by berberine. Moreover, berberine changed the overall gut microbial community, primarily increased the abundance of Akkermansia muciniphila. Of note, depletion of gut microbiota abolished the inducing effect of berberine on G‐MDSC‐like population, and attenuated its hepatoprotective effect against alcohol in mice, suggesting intestinal flora might be involved in mediating the expansion of this protective population. Conclusion Collectively, this study delivered insight into the role of immunosuppressive response in ALD, and facilitated the understanding of the pharmacological effects and action mechanisms of berberine.

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Section: Berberine Induced G-mdsc-like Cells Expansion In Niaaa Micementioning

confidence: 99%

Modulation of gut microbiota mediates berberine‐induced expansion of immuno‐suppressive cells to against alcoholic liver disease

Wang

Tan

et al. 2020

Clinical & Translational Med

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“…Similarly, the recovery of structural brain alterations can be highly variable depending on brain areas and individual features (Durazzo et al, 2015; Zou et al, 2018). Overall, both ARLD and ARBI involve alcohol-related inflammatory processes (Mandrekar and Ambade, 2014; Neupane, 2016). Current medications for reducing alcohol drinking or supporting alcohol abstinence in AUD subjects are still insufficiently effective at a population level, and new therapeutic prospects are needed (Rolland et al, 2016; Soyka and Müller, 2017).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on the Liver and the Brain

Ternay¹,

Naassila

Nourredine³

et al. 2019

Front. Pharmacol.

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Background: Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver. Aim: To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies. Methods: Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD. Results: Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties. Conclusions: CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual’s drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.

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“…It is likely that sensitization to TLR ligands is regulated by multiple mechanisms, including activation by endogenous danger signals from damaged cells in ALD . The latter may trigger immune reactions in the liver that are different in humans and rodents in accordance with their different immune and TLR systems …”

Section: Discussionmentioning

confidence: 99%

“…(29) The latter may trigger immune reactions in the liver that are different in humans and rodents in accordance with their different immune and TLR systems. (9,10,30) Endogenous danger signals released from damaged cells can also activate the inflammatory cascade. Although a proinflammatory response occurred in liver-resident macrophages, the IL-6/Stat3 pathway was surprisingly blunted in parenchymal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, differences exist between the murine and human immune systems as well as in the capacity of immune cells to respond to damage‐associated molecular patterns, such as toll‐like receptors (TLRs) that are expressed at the cell surface in macrophages (13 in rodents, 10 in humans) . For these reasons and also because alcohol‐induced inflammation, crucial in the onset and progression of ALD, implicates multiple hepatic cell types as well as innate and adaptive immune responses, studies directly conducted in humans are mandatory. However, human studies are scarce, and those available focus on severe alcoholic hepatitis, a condition for which liver biopsies and data are more readily available than for early ALD.…”

mentioning

confidence: 99%

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Deficient IL‐6/Stat3 Signaling, High TLR7, and Type I Interferons in Early Human Alcoholic Liver Disease: A Triad for Liver Damage and Fibrosis

et al. 2019

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Mechanisms underlying alcohol‐induced liver injury and its progression still remain incompletely understood. Animal models can only address some aspects of the pathophysiology that requires studies directly in humans, which are scarce. We assessed liver inflammatory and immune responses at early stages of alcoholic liver disease in a unique cohort of alcohol‐dependent patients undergoing a highly standardized alcohol withdrawal program. In active drinkers, quantitative real‐time polymerase chain reaction revealed alcohol‐induced activation of tumor necrosis factor alpha, interleukin (IL)‐1β, and nuclear factor kappa B in liver tissue already at early disease stages. Double immunofluorescence staining indicated that this proinflammatory response was restricted to activated, CD68‐positive macrophages. In parallel, down‐regulation of IL‐6, inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway, as well as blunted cyclin D expression in hepatocytes, reduced proliferation and favored hepatocyte apoptosis. In addition, immunofluorescence and quantitative real‐time polymerase chain reaction of liver tissue showed that alcohol also activated the toll‐like receptor (TLR) 7–interferon (IFN) axis in hepatocytes, which was confirmed in alcohol‐stimulated primary human hepatocytes and precision‐cut liver slices in vitro . Activation of the TLR7–IFN axis strongly correlated with liver fibrosis markers and disease progression. Two weeks of abstinence attenuated the inflammatory response but did not allow recovery of the defective Stat3 pathway or effect on fibrosis‐associated factors. Conclusion : In humans, inflammation, activation of the TLR7–IFN axis, and inhibition of Stat3‐dependent repair mechanisms in early alcoholic liver disease pave the way for fibrosis development and ultimately disease progression.

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Immunity and inflammatory signaling in alcoholic liver disease

Cited by 14 publications

References 53 publications

Modulation of gut microbiota mediates berberine‐induced expansion of immuno‐suppressive cells to against alcoholic liver disease

Modulation of gut microbiota mediates berberine‐induced expansion of immuno‐suppressive cells to against alcoholic liver disease

Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on the Liver and the Brain

Deficient IL‐6/Stat3 Signaling, High TLR7, and Type I Interferons in Early Human Alcoholic Liver Disease: A Triad for Liver Damage and Fibrosis

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