IRF5:RelA interaction targets inflammatory genes in macrophages

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Interferon Regulatory Factor 5 (IRF5) is crucial for inflammatory macrophage phenotypes.
• The precise molecular mechanisms governing IRF5's transcriptional activity remain incompletely understood.

Purpose of the Study:

• To perform a genome-wide analysis of IRF5 recruitment in lipopolysaccharide-stimulated macrophages.
• To elucidate the molecular basis of IRF5's transcriptional activity and its interactions with other proteins.

Main Methods:

• Genome-wide analysis of IRF5 recruitment.
• Protein:DNA microarray analysis.
• Global gene expression analysis in IRF5 and RelA deficient macrophages.

Main Results:

• IRF5 binds to regulatory elements of highly transcribed genes.
• In vitro, IRF5 recognizes the canonical ISRE motif, but in vivo binding depends on protein interactions.
• IRF5 binds a noncanonical PU.1:ISRE motif, facilitated by RelA.
• The RelA:IRF5 cistrome directly regulates key inflammatory genes.

Conclusions:

• IRF5's in vivo function is mediated by interactions with other proteins, notably RelA.
• The RelA:IRF5 interaction is critical for regulating a subset of inflammatory genes.
• Targeting the RelA:IRF5 interaction domain could selectively modulate macrophage inflammatory responses.