Proinflammatory Genes are Transcriptionally Suppressed by Type I Interferon Through Undescribed Non-canonical Mechanisms 2259728

Abstract Introduction Type I interferons (IFN) are crucial for effective antiviral immune responses. Paradoxically, they exhibit poorly defined immunosuppressive properties in conditions such as bacterial infections or multiple sclerosis. Previous work has shown that IFNβ suppresses transcription of key proinflammatory genes leading to immunosuppression; however, the total repertoire of genes impacted is unknown. Methods To determine the immune response genes transcriptionally suppressed by IFNβ, RNA sequencing was performed on bone marrow—derived macrophages (BMDMs) pretreated with IFNβ prior to stimulation with ligands for two distinct Toll-like receptors (TLRs). Results Differential expression analysis revealed that IFNβ pretreatment reprograms TLR-induced transcriptional responses, uncovering a unique coordinately regulated cluster of TLR-induced genes suppressed by IFNβ that lack shared promoter-proximal sequence motifs. Pathway enrichment analysis indicated preferential suppression of immune-related pathways, including cytokine—cytokine receptor interactions, IL-17 signaling, and neutrophil chemotaxis. Although IFNs are known to positively regulate gene expression via the ISGF3 complex, IFNβ-mediated transcriptional suppression persisted in STAT1- and STAT2-deficient BMDMs, suggesting an alternative regulatory complex. Conclusion This study defines a novel population of type I interferon—inhibited genes (TIIGs) regulated independently of ISGF3, further defining IFN’s role in non-viral inflammation. Funding Source R21 AI180181-01 T32 AI095190 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)