Our findings indicate that type 1 interferon (IFN-α/β) signaling, along with the type 2 interferon (IFN-γ) pathway, are regulated by alternative splicing in AUD. For each of the five exon skipping events, their respective downstream genes were enriched in IFN-α/β/γ signaling pathways. The IFN-α/β pathway was found to be affected by alcohol in a previous cell culture study [57]. In addition, our findings provide further evidence for the relevance of neuroimmune pathways to AUD, including the TNF, NF-κB, IL6-JAK-STAT3, IL2-STAT5, and NOD-like receptor (NLR) signaling pathways, as well as T cell activation and differentiation, because they are regulated by one or more of these five splicing events. These neuroimmune pathways have previously been shown to be responsive to alcohol [57, 77]. Our results also showed that the exon skipping events in ELOVL7, LINC00665, NSUN4, and SRRM2 implicate the complement cascade, which is part of the innate immune system. While the complement cascade is known to be involved in alcoholic liver disease, it also participates in neurodevelopment and protects the central nerve system from inflammation [78]. Taken together, our findings further support the relevance of inflammatory cytokine-induced immune response to AUD.
