PRMT6 suppresses intestinal inflammation by epigenetically repressing IL-1β in mouse models of colitis

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder driven by dysregulated immune responses. Macrophage-mediated inflammation is central to the pathology, and it is important to understand the epigenetic mechanisms involved. By screening epigenetic molecules that are differentially expressed in published human IBD datasets, we find Protein Arginine Methyltransferase 6 (PRMT6) consistently downregulated in IBD samples compared to healthy controls. Co-occurrence of Prmt6 suppression and Il1b induction within the myeloid compartment in colon biopsy samples indicates that PRMT6 limits macrophage-driven inflammation. Concordantly, Prmt6-deficient mice exhibit increased susceptibility to both DSS- and TNBS-induced colitis, characterized by exacerbated tissue damage and systemic elevation of IL-1β. Transcriptomic profiling confirms that PRMT6 deficiency selectively upregulates Il1b among inflammatory mediators. Mechanistically, PRMT6 suppresses Il1b transcription by interacting with RBBP5 and disrupting SET1A complex assembly, thereby reducing H3K4me3 enrichment at the Il1b promoter, independently of its canonical H3R2me2a catalytic activity. Furthermore, PRMT6 is transcriptionally silenced by the NF-κB subunit p50 during inflammation. Pharmacological inhibition of p50 restores PRMT6 expression, thus protecting mice from DSS-induced colitis in a PRMT6-dependent manner. Our findings highlight PRMT6 as a pivotal epigenetic regulator of the inflammatory response and provide proof of principle for targeting the p50–PRMT6–IL-1β axis in IBD. Epigenetic regulation in immune cells drive their physiological and pathologic development, including establishment of inflammatory states. Here the authors show in mouse colitis models, that genomic deletion of the protein arginine methyltransferase PRMT6 leads to a selective upregulation of IL-1β in macrophages and to exacerbated inflammation.