Epigenomic landscapes define differential Janus kinases inhibitor sensitivity in IFN-γ-primed human macrophages

Janus kinases (JAK) mediate signaling pathways of multiple cytokines, including interferon-γ (IFN-γ), which plays a pivotal role in rheumatoid arthritis (RA) pathogenesis. Although JAK inhibitors (JAKi) have demonstrated efficacy for RA, their molecular effects on macrophages remain incompletely understood. We investigate the impact of JAKi on IFN-γ-induced gene expression in human macrophages, uncovering that JAKi selectively modulates only a subset of IFN-γ-induced genes. Integrated transcriptomic and epigenomic analyses demonstrate that JAKi effectively inhibits IFN-γ signature genes associated with IRF1-STAT1-dependent accessible chromatin regions. However, genes regulated by AP-1 and C/EBP remain insensitive to JAKi and overlap significantly with TNF-induced genes. Single-cell analysis of RA patient samples identifies macrophage subpopulations with variable JAKi sensitivity. Certain JAKi-insensitive genes in IFN-γ-primed macrophages are suppressed by JNK inhibitors. Our findings elucidate JAKi responsiveness mechanisms through IFN-γ-induced epigenomic remodeling, providing insights into inflammatory regulation in RA and suggesting strategies to overcome JAKi resistance.