Sexual dimorphism of the dysregulated lung immunometabolism and immunity induced by chronic alcohol consumption

Authors

• L Pommerolle
• M Arif
• M Behee
• C Appolonia
• A Basu
• KM Wolf
• CN Zawatsky
• N Johnson
• O Rivellini
• JK Park
• R Cinar

Abstract

Chronic alcohol consumption impairs lung immunity which makes individuals with AUD more susceptible to developing inflammatory lung conditions and leads to acute respiratory distress syndrome. However, there is no clearly identified mechanism for how the lung immunity is compromised by chronic alcohol drinking. We focused on investigating the molecular and cellular effects of alcohol ingestion on lung immunity in male and female subjects using population-based human lung transcriptomics data from the Genotype-Tissue Expression (GTEx) project, encompassing 328 alcohol drinkers and 110 nondrinkers and an experimental mouse model of chronic alcohol drinking using the NIAAA alcohol feeding model. We demonstrated males are more sensitive than females to the effects of chronic alcohol drinking on down-regulating lung immunity in both, human and mouse. Flow cytometry indicated that innate and adaptative immunity were dysregulated in the lung. Transcriptomic data from lungs and liver mice at 9-, 24- hours, and 14 days post-binge alcohol revealed that the lungs were more sensitive to alcohol effect to down-regulate pathways of immune system regulations than the liver.
Comparative analysis of lung transcriptomes between mice and human subjects highlighted similar dysregulation in lung immunity, with the downregulation of immune pathways and the upregulation of metabolic pathways, suggesting immunometabolic involvement. Additionally, we identified the branch-chain amino acid/mTOR signaling axis as a pivotal upstream regulator in the dysregulation of lung immunity. Accordingly, restoring the balance between mTOR signaling and BCAA degradation might be essential for developing viable therapeutic strategies in alcohol-induced lung injury.

Scientific Focus Area: Immunology

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