Macrophages play a critical role in the immune homeostasis and host defense against invading pathogens. However, uncontrolled activation of inflammatory macrophages leads to tissue injury and even fuels autoimmunity. Hence the molecular mechanisms underlying macrophage activation need to be further elucidated. The effects of epigenetic modifications on the function of immune cells draw increasing attention. Here, we demonstrated that lysine-specific demethylase 5B (KDM5B), a classical transcriptional repressor in stem cell development and cancer, was required for the full activation of NF-κB signaling cascade and pro-inflammatory cytokine production in macrophages. KDM5B deficiency or inhibitor treatment protected mice from immunologic injury in both collagen-induced arthritis (CIA) model and endotoxin shock model. Genome-wide analysis of KDM5B-binding peaks identified that KDM5B was selectively recruited to the promoter of Nfkbia, the gene encoding IκBα, in activated macrophages. KDM5B mediated the H3K4me3 modification erasing and decreased chromatin accessibility of Nfkbia gene locus, coordinating the elaborate suppression of IκBα expression and the enhanced NF-κB-mediated macrophage activation. Our finding identifies the indispensable role of KDM5B in macrophage-mediated inflammatory responses and provides a candidate therapeutic target for autoimmune and inflammatory disorders.
© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.