IL-10 Targets IRF1/5 to Suppress IFN and Inflammatory Responses by Epigenetic Mechanisms [Cut & Run]

Interleukin-10 (IL-10) is pivotal in suppressing inflammation and innate immune activation, in large part by suppressing induction of genes by potent inflammatory factors such as TLR ligands. Despite decades of research, molecular mechanisms underlying this inhibition have not been resolved. This study utilized an integrated epigenomic analysis of gene transcription, chromatin accessibility, histone modifications and transcription factor binding to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-kB, MAPK-AP-1 and TBK1-IRF3 signaling, IL-10 targeted IRF5 an IRF1-mediated amplification loop that is important for IFNB, ISG and inflammatory gene induction in monocytes. This resulted in near-complete suppression of ISGs, and significant inhibition of inflammatory NF-kB target genes, in whose activation IRFs play an amplifying role. Mechanisms of TLR4 and TNFR target gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation, and IRF1-associated H3K27ac activating histone marks. These results describe an underappreciated suppression of IFN responses by IL-10 and provide epigenetic mechanisms by which IL-10 suppresses TLR/TNF-induced gene expression.