Abstract
Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra-/-) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.
Highlights
Alcohol use disorder is a chronic, relapsing disorder manifested by repetitive and compulsive consumption of alcohol, followed by a dysregulated emotional state during abstinence [1]
Hepatic expression of IL-17A and IL-17RA mRNA were progressively increased in mice with acute (2 -fold) or chronic (3-fold) alcoholic steatohepatitis (ASH) and alcohol-induced liver fibrosis (3- to 6-fold), compared with the corresponding pair-fed controls (Figure 1), suggesting that activation of IL-17 signaling correlates with the severity of alcohol-induced liver injury in mice
Blockade of IL-17A either genetically or pharmacologically inhibits development of alcohol-induced liver fibrosis and suppresses excessive alcohol drinking in mice via preventing astrocytic reactivity
Summary
Alcohol use disorder is a chronic, relapsing disorder manifested by repetitive and compulsive consumption of alcohol, followed by a dysregulated emotional state during abstinence [1]. Patients addicted to alcohol often develop alcoholic liver disease (ALD), which progresses from steatosis to steatohepatitis and cirrhosis [3]. Loss of detoxifying functions in the alcohol-damaged liver results in release of hepatotoxins and microbial metabolites into circulation and development of systemic inflammation [4] that further increases permeability of the blood-brain barrier (BBB), facilitates alcohol-induced brain injury [5], and as a result, may perpetuate and promote the addictive behavior. No common underlying mechanism for alcohol-induced liver/brain injury and alcohol addiction has been identified
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