Macrophage-specific targeting of histone demethylases with small-molecule inhibitors suppresses inflammatory responses in vivo [CUT&Run]

A complex network of epigenetic processes, such as DNA methylation, histone methylation, and acetylation, play key roles in modulating macrophage polarization and inflammatory gene expression. Transcriptional analysis in patients with respiratory failure, long COVID-19, and influenza revealed an augmented expression of chromatin-modifiers including histone demethylases, broadly defined as lysine demethylases (KDMs), in lung macrophages.

Therefore, macrophage-specific pharmacological perturbation of these enzymes in vivo holds therapeutic promise in abating inflammation. To investigate the role of KDMs in inflammation, we screened a panel of small-molecule inhibitors of chromatin modifiers for their efficacy in inducing anti-inflammatory macrophage polarization in vitro. We demonstrate that pretreatment with the broad spectrum KDM inhibitor n-octyl-IOX1, KDM5-specific inhibitor PB-IT resulted in a significant decrease of lipopolysaccharide (LPS)-induced expression of the inflammatory genes Il1b, Il6, Tnfa, and iNos in bone marrow-derived macrophages (BMDM).