Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders

摘要

Alcohol use disorder (AUD) is a primary, chronic and relapsing disease of brain reward, motivation and memory, which is associated with several comorbidities, including major depression and post-traumatic stress disorder. It has been revealed that Ibudilast (IBUD), a dual inhibitor of phosphodiesterase-4 and -10 and of macrophage migration inhibitory factor (MIF), exerts beneficial effects on AUD in rodent models and human patients. Therefore, IBUD has attracted increasing interest, with research focusing on the elucidation of the pathogenic role of MIF and its homologue, D-dopachrome tautomerase (DDT), in the pathogenesis and maintenance of AUD. By using DNA microarray analysis, the current study performed a transcriptomic expression analysis of MIF, DDT and their co-receptors, including CD74, C-X-C chemokine receptor (CXCR)2, CXCR4 and CXCR7 in patients with AUD. The results revealed that the transcriptomic levels of MIF, DDT and their receptors were superimposable in the prefrontal cortex of rodents and patients with AUD and human patients. Furthermore, peripheral blood cells from heavy drinkers exhibited a moderate increase in MIF and DDT levels, both at the baseline and following exposure to alcohol-associated cues, based on individual situations that included alcohol-related stimuli resulting in subsequent alcohol use (buying alcohol and being at a bar, watching others drink alcohol). Considering the overlapping effects of MIF and DDT, the inverse Fisher's chi(2) test was performed on unadjusted P-values to evaluate the combined effect of MIF and DDT. The results revealed a significant increase in these cytokines in heavy drinkers compared with controls (moderate drinkers). To the best of our knowledge, the present study demonstrated for the first time that MIF and DDT expression was upregulated in the blood of patients with AUD. These results therefore warrant further study to evaluate the role of MIF and DDT in the development and maintenance of AUD, to evaluate their use as biomarkers to predict the psychotherapeutic and pharmacological response of patients with AUD and for use as therapeutic targets.