BHLHE40 promotes macrophage pro-inflammatory gene expression and functions

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Macrophages are key innate immune cells crucial for host defense against pathogens and injury.
• Effective inflammatory responses rely on precise transcriptional regulation of immune and metabolic genes.
• Transcription factors play a vital role in orchestrating these complex cellular processes.

Purpose of the Study:

• To identify novel transcription factors regulating macrophage pro-inflammatory and metabolic gene expression.
• To investigate the role of BHLHE40 (basic helix-loop-helix family member e40) in macrophage activation.
• To elucidate the mechanism by which BHLHE40 influences inflammatory responses.

Main Methods:

• In vivo studies using myeloid-BHLHE40 deficient mice.
• Integrated transcriptomics and gene set enrichment analysis (GSEA).
• Complementary gain- and loss-of-function studies in macrophages.
• Analysis of HIF1α (hypoxia-inducible factor 1-alpha) mRNA and protein expression.

Main Results:

• Myeloid-BHLHE40 deficiency significantly reduced macrophage and neutrophil recruitment to inflammatory sites.
• BHLHE40 deficiency broadly suppressed inflammatory signaling, hypoxia response, and glycolytic gene expression in macrophages.
• BHLHE40 was found to promote LPS-induced HIF1α mRNA and protein expression.
• Overexpression of HIF1α rescued the attenuated pro-inflammatory and glycolytic gene expression in BHLHE40-deficient macrophages.

Conclusions:

• BHLHE40 is a critical transcription factor that promotes pro-inflammatory and glycolytic gene expression in macrophages.
• BHLHE40 functions by elevating HIF1α levels, thereby regulating the macrophage inflammatory response.
• These findings highlight BHLHE40 as a potential therapeutic target for modulating inflammatory diseases.