Restricted immunological and cellular pathways are shared by murine models of chronic alcohol consumption

Abstract

Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Lieber-DeCarli diet (LD) and Meadows-Cook diet (MC) are the most accepted models of chronic alcohol consumption. It is unclear how similar these models are at the cellular, immunologic, and transcriptome levels. We investigated the common and specific pathways of LD and MC models. Livers from LD and MC mice were subjected to histologic changes, hepatic leukocyte population, hepatic transcripts level related to leukocyte recruitment, and hepatic RNA-seq analysis. Cross-species comparison was performed using the alcoholic liver disease (ALD) transcriptomic public dataset. Despite LD mice have increased liver injury and steatosis by alcohol exposure, the number of CD45 + cells were reduced. Opposite, MC mice have an increased number of monocytes/liver by alcohol. The pattern of chemokine gradient, adhesion molecules, and cytokine transcripts is highly specific for each model, not shared with advanced human alcoholic liver disease. Moreover, hepatic RNA-seq revealed a limited and restricted number of shared genes differentially changed by alcohol exposure in these 2 models. Thus, mechanisms involved in alcohol tissue injury are model-dependent at multiple levels and raise the consideration of significant pathophysiological diversity of human alcoholic liver injury. Murine models are frequently used to investigate new pathophysiological pathways of human diseases and many new treatment trials for alcoholic liver disease (ALD) are based on preclinical testing provided by murine models. ALD in humans is the result of a complex interaction between the alcoholic effects on gut microbiota, intestinal cells, immune system, and the hepatic microenvironment 1,2. Based on an extensive body of literature, alcohol increases the intestinal permeability and subsequent systemic translocation of bacterial products, e.g. LPS 1,3,4. Stimulation of Toll-like receptors (TLR) by bacterial products results in immune cell activation related to hepatic alcohol metabolic process that has a deleterious effect on the liver, resulting in histological features of ALD: steatosis, innate immune infiltrate with predominance of neutrophils and monocytes, and histological signs of hepatocyte dysfunction (Mallory hyaline formation, ballooning hepatocyte) 3,5-7. ALD includes a spectrum of histological and clinical entities: steatosis, steatohepatitis, and alcoholic hepatitis 8,9. In time, chronic liver injury with a dysregulated innate immune response results in alcohol-induced progressive hepatic fibrogenesis, liver cirrhosis and end-stage liver disease 10. Based on this classical paradigm, few trials have been attempted to control an exacerbated innate immune response or to improve hepatocyte function. Besides steroids that may be beneficial for only subsets of patients with alcoholic hepatitis 11 , no other treatments have proven consistent survival benefit 12. Moreover, treatment of anti-TNFα in alcoholic hepati...

Murine Models of Alcohol Consumption: Imperfect but Still Potential Source of Novel Biomarkers and Therapeutic Drug Discovery for Alcoholic Liver Disease

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The histological phenotype in LD exposed mice with or without alcohol showed more steatosis than MC mice [2,3]. This is expected considering the liquid high fat diet in LD.

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“…Although none of the animal models available reproduce all main aspects of human ALD, they still provide very useful tools to study and understand the molecular mechanisms of the human counterpart [2]. There are two well accepted and commonly used murine models of chronic alcohol consumption introduced by Meadows-Cook (MC) and Lieber-DeCarli (LD) [2,3]. In the MC model, alcohol is introduced in drinking water, in a final concentration increased gradually to reach 20% in most cases [2,4].…”

“…In the MC model, alcohol is introduced in drinking water, in a final concentration increased gradually to reach 20% in most cases [2,4]. Mice kept in the MC model for up to 16 weeks; however, most studies use 12 weeks as the final readout point [3]. LD was developed to enhance the alcoholic liver injury phenotype in mice [2,5].…”

Alcohol Consumption Accumulation of Monocyte Derived Macrophages in Female Mice Liver Is Interferon Alpha Receptor Dependent

“…We chose MC, not Lieber DeCarli (LD), the most common mouse model of chronic alcoholic liver injury, because we are interested in studying the specific effect of alcohol on immune cells without the interference of the high fat and liquid diet used in LD model. Moreover, previous work published by our group demonstrated that LD model shared with alcohol exposure alone only a very restricted number of altered pathways (24).…”

“…To investigate the effect of alcohol consumption on monocytes homeostasis, female and male mice received alcohol in drinking water per Meadows-Cook (MC) model, a well-accepted mouse model of chronic alcohol consumption to characterize immunological effects of alcohol (23,24). We chose MC, not Lieber DeCarli (LD), the most common mouse model of chronic alcoholic liver injury, because we are interested in studying the specific effect of alcohol on immune cells without the interference of the high fat and liquid diet used in LD model.…”