Abstract NLRP3 inflammasome, the archetypical molecular driver of inflammation, plays crucial roles in host defense and maintaining cellular homeostasis. Demethylation of histone 3 lysine 9 trimethylation (H3K9me3, the repressive mark for euchromatic genes) is essential for activating gene transcription. However, whether H3K9 demethylation is required for the induction of proinflammatory cytokines remains largely unknown. Here, we show that histone demethylase lysine-specific demethylase 4B (KDM4B) mediates H3K9me3 demethylation at the Nlrp3 promoter to induce NLRP3 expression, thereby selectively enhancing NLRP3 inflammasome activation without affecting NF-κB activation. Concordantly, both Kdm4b deficiency and the selective KDM4 inhibitor ML324 inhibit NLRP3 inflammasome activation and ameliorate NLRP3-dependent inflammatory diseases in vivo. Furthermore, high glucose level upregulates KDM4B, promoting NLRP3 inflammasome activation and IL-1β secretion, thus aggravating aberrant inflammation during viral infections. Our findings reveal the role of H3K9me3 demethylation in initiating inflammation, identify KDM4B as an epigenetic accelerator of NLRP3, and propose that modulating H3K9me3 could represent a targeted anti-inflammatory strategy.
Tong et al. (Tue,) studied this question.