Network meta‐analysis of the molecular mechanisms and signaling pathways underlying alcohol‐induced thymic atrophy

Abstract

AbstractBackgroundThymic atrophy is characterized by loss of thymocytes, destruction of thymic architecture, and a subsequent decrease in naïve T cells with compromised immunity. Thymic atrophy occurs during aging. Environmental factors including alcohol misuse also induce thymic atrophy. Despite the link between alcohol misuse and thymic atrophy, the underlying mechanism is understudied. We aimed to identify molecules and signaling pathways that underly alcohol‐induced thymic atrophy during aging.MethodsF344 rats were given 3‐day binge‐ethanol (4.8 g/kg/day; 52% w/v; i.g.) and the thymus was collected and weighed. Molecular mechanisms underlying ethanol‐induced thymic atrophy were investigated by network meta‐analysis using the QIAGEN Ingenuity Pathway Analysis (IPA). The molecules associated with ethanol were identified from the QIAGEN Knowledge Base (QKB) and those associated with thymic atrophy were identified from QKB and Mouse Genome Informatics (MGI). Aging‐mediated Differential Expression Genes (DEGs) from mouse thymocytes were obtained from the Gene Expression Omnibus (GEO) database (GSE132136). The relationship between the molecules and associated signaling pathways were studied using IPA.ResultsBinge‐ethanol decreased thymic weight in F344 rats. Our meta‐analysis using IPA identified molecules commonly shared by ethanol and thymic atrophy through which simulation with ethanol increased thymic atrophy. We then obtained aging‐mediated DEGs from the atrophied thymocytes. We found that ethanol contributed to thymic atrophy through modulation of the aging‐mediated DEGs. Our network meta‐analysis suggests that ethanol may augment thymic atrophy through increased expression of cytokines (e.g., IL‐6, IL‐17A and IL‐33) along with their regulators (e.g., STAT1 and STAT3).ConclusionsExposure to alcohol may augment thymic atrophy by altering the activity of key inflammatory mediators, such as STAT family members and inflammatory cytokines. These findings provide insights into the signaling pathways and upstream regulators that underly alcohol‐induced thymic atrophy during aging, suggesting that alcohol consumption could prepone thymic atrophy.