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

Alyx Vogle,Tongqi Qian,Elizabeth Burnett,Costica Aloman,Maliha Shaikh,Zhibin Zhu,Miran Kim,Yujin Hoshida,Ali Keshavarzian,Holger Fey,Shijia Zhu

doi:10.1038/s41598-020-59188-9

Alyx Vogle, Tongqi Qian + Show 9 more

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https://doi.org/10.1038/s41598-020-59188-9

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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.

Highlights

Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets
The duration of exposure to alcohol for the Meadows-Cook diet (MC) model was extended to 12 weeks instead of 4 weeks based on the previous literature data supporting the presence of clear cut alcohol related immunological effects after this time period[17], as www.nature.com/scientificreports well as our own validation
Despite longer duration of exposure to alcohol, as reported in the literature[31,32], only alcohol added to Lieber-DeCarli diet (LD) diet increases hepatic steatosis severity estimated by pathological score (Fig. 1B) while no significant difference is grossly noted by histology in mice exposed to alcohol in MC model (Supplementary Figs. 2 and 3)

Summary

Introduction

Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Treatment of anti-TNFα in alcoholic hepatitis patients, based on extensive data supporting the pathogenic role of this cytokine and initial exciting preliminary outcome[13], showed a paradoxical increase of patient mortality due to infections[14]. These despairing circumstances, corroborated with new insights into differences between human and mouse immune system[15,16], prompted our hypothesis that only limited pathophysiological pathways may be shared between human ALD and different murine models of chronic alcohol consumption routinely used in preclinical studies. The primary goal of our study was to identify the degree of cellular, immunological, and transcriptional similarity profiles between two of the most common murine models of chronic alcohol exposure; secondarily, we compared both murine models at the transcriptional level with the most severe form of human ALD, alcoholic hepatitis, to depict if common pathways are present in these early models of alcohol hepatic toxicity and alcoholic hepatitis

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