# Histone demethylase KDM4B epigenetically controls NLRP3 expression to enhance inflammatory responses

## TL;DR

This study shows that the enzyme KDM4B boosts inflammation by activating the NLRP3 inflammasome through epigenetic changes, suggesting KDM4B inhibitors could treat inflammatory diseases.

## Contribution

The study identifies KDM4B as a novel epigenetic regulator of NLRP3 inflammasome activation through H3K9me3 demethylation.

## Key findings

- KDM4B promotes NLRP3 expression by demethylating H3K9me3 at the Nlrp3 promoter.
- KDM4B inhibition or deficiency reduces NLRP3-dependent inflammation in vivo.
- High glucose levels increase KDM4B activity, worsening inflammation during viral infections.

## 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.

The histone demethylase lysine-specific demethylase 4B (KDM4B) is identified as an epigenetic activator of the NLRP3 inflammasome, suggesting KDM4B inhibition as a therapeutic strategy for NLRP3-driven inflammatory pathologies.

KDM4B selectively enhances NLRP3 inflammasome activation by promoting Nlrp3 transcription, without affecting NF-κB activation.Kdm4b deficiency and the selective KDM4 inhibitor ML324 both inhibit NLRP3 inflammasome activation and reduce NLRP3-dependent inflammatory diseases in vivo.KDM4B mediates the demethylation of H3K9me3 at the Nlrp3 promoter to induce NLRP3 expression.High glucose concentrations upregulate KDM4B to promote NLRP3 inflammasome activation and control the severity of the inflammation during viral infection.

KDM4B selectively enhances NLRP3 inflammasome activation by promoting Nlrp3 transcription, without affecting NF-κB activation.

Kdm4b deficiency and the selective KDM4 inhibitor ML324 both inhibit NLRP3 inflammasome activation and reduce NLRP3-dependent inflammatory diseases in vivo.

KDM4B mediates the demethylation of H3K9me3 at the Nlrp3 promoter to induce NLRP3 expression.

High glucose concentrations upregulate KDM4B to promote NLRP3 inflammasome activation and control the severity of the inflammation during viral infection.

The histone demethylase lysine-specific demethylase 4B (KDM4B) is identified as an epigenetic activator of the NLRP3 inflammasome, suggesting KDM4B inhibition as a therapeutic strategy for NLRP3-driven inflammatory pathologies.