Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• Macrophages are crucial for immune responses but their overactivation drives tissue injury and autoimmunity.
• Understanding the molecular mechanisms of macrophage activation, particularly epigenetic regulation, is essential.

Purpose of the Study:

• To elucidate the role of lysine-specific demethylase 5B (KDM5B) in macrophage activation and inflammatory responses.
• To investigate KDM5B's potential as a therapeutic target for inflammatory and autoimmune disorders.

Main Methods:

• Utilized mouse models of collagen-induced arthritis (CIA) and endotoxin shock.
• Performed genome-wide analysis to identify KDM5B binding sites.
• Assessed epigenetic modifications (H3K4me3) and chromatin accessibility at the Nfkbia locus.
• Measured NF-κB signaling and pro-inflammatory cytokine production.

Main Results:

• KDM5B deficiency or inhibition protected mice from immunologic injury in CIA and endotoxin shock models.
• KDM5B was recruited to the Nfkbia promoter in activated macrophages.
• KDM5B mediated H3K4me3 erasure and reduced chromatin accessibility at Nfkbia, suppressing IκBα expression.
• This suppression enhanced NF-κB-mediated macrophage activation and pro-inflammatory cytokine production.

Conclusions:

• KDM5B plays an indispensable role in regulating macrophage activation and inflammatory responses.
• KDM5B's epigenetic regulation of Nfkbia is critical for NF-κB pathway activation.
• KDM5B represents a promising therapeutic target for autoimmune and inflammatory diseases.