Selective epigenetic regulation of IFN-γ signature genes by JAK inhibitor in inflammatory diseases

This study addresses the molecular mechanisms behind JAK inhibitors (JAKi)' epigenetic regulation of IFN-γ-induced genes in macrophages, key players in controlling inflammation in chronic diseases such as rheumatoid arthritis (RA) and COVID-19. Utilizing transcriptomic and epigenomic approaches, we reveal that JAKi selectively regulate gene programs in IFN-γ-activated human macrophages. Our single-cell analysis identified high expression of IFN-γ signature genes in macrophages from RA and severe COVID-19 patients. JAKi suppressed some inflammatory genes, while a subset remained unresponsive to JAK-STAT inhibition. We discovered that JAKi selectively target IRF-STAT-dependent open chromatin regions, leaving AP-1-C/EBP-regulated genes with open chromatin unaffected. Some JAKi-insensitive genes could be inhibited by JNK inhibitors in IFN-γ-primed macrophages. Our analysis also identified JAKi-sensitive and -insensitive IFN-γ signature genes in RA patients resistant to MTX treatments and COVID-19 vaccinated donors, highlighting JAKi's therapeutic potential and risks. These findings uncover new JAKi responsiveness mechanisms through epigenomic changes in IFN-γ-primed macrophages, advancing our understanding of inflammation regulation in chronic diseases.