Sexually dimorphic effect of chronic alcohol drinking on dysregulating lung immunity by altering immunometabolism in human and mouse

Heavy alcohol drinking alters lung immunity increasing the susceptibility to inflammatory and fibroproliferative conditions with poor prognoses. Although a sexually dimorphic effect was demonstrated in different organs, gender difference was not clearly demonstrated in lung immunity. Here, 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 analysis and an experimental mouse model of chronic alcohol drinking. Human lung transcriptomics data were analyzed from 328 alcohol drinkers (249 males and 79 females) and 110 nondrinkers (53 males and 57 females) using Genotype-Tissue Expression (GTEx) project data. The translational relevance was established with the NIAAA alcohol-feeding model in mice. Flow cytometry and transcriptomics analyses in mice revealed a sexually dimorphic effect of chronic alcohol drinking on the lung immunity of both humans and mice. Dose dependently chronic alcohol drinking significantly down-regulated immune-related pathways only in male human subjects. Both myeloid and lymphoid cells were altered only in male lungs. In addition, the different subpopulations of lung macrophages, as well as their polarization (CD206/CD80), were impaired in male mice with a moderate effect in females. Transcriptomics analysis from humans and mice provided evidence that immunometabolic change is a central driver. The Branch Chain Amino Acid-mTOR signaling axis may serve as an upstream regulator of alcohol-induced dysregulation in lung immunity.