Histone demethylase KDM4B epigenetically controls NLRP3 expression to enhance inflammatory responses

Abstract

NLRP3 inflammasome, as the archetypical molecular driver of inflammatory response, plays crucial roles in host defense and the maintenance of cell homeostasis. The demethylation of trimethylation of lysine 9 at histone 3 (H3K9me3, the repressive mark for euchromatic genes) is a prerequisite for the transcription of most genes. However, whether H3K9 demethylation is required for the induction of proinflammatory cytokines remains unknown. Here, we show that histone demethylase lysine-specific demethylase 4B (KDM4B) mediates demethylation of H3K9me3 at the Nlrp3 promoter to induce NLRP3 expression. It therefore selectively enhances NLRP3 inflammasome activation without affecting NF-κB activation. Concordantly, Kdm4b deficiency and the selective KDM4 inhibitor ML324 both inhibit NLRP3 inflammasome activation and ameliorate NLRP3-dependent inflammatory diseases in vivo. Moreover, high glucose upregulates KDM4B to promote NLRP3 inflammasome activation and IL-1β secretion, and therefore aggravates viral infection-induced aberrant inflammation. Therefore, we determine the role of H3K9me3 demethylation in initiating inflammation, identify KDM4B as an epigenetic enhancer of NLRP3, and suggest modulating H3K9me3 might be an anti-inflammatory strategy with better selectivity.