Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype

Area of Science:

• Molecular Biology
• Immunology
• Metabolic Diseases

Background:

• Obesity-associated metabolic inflammation involves proinflammatory macrophages in adipose tissue.
• The translation factor eIF5A, modified by deoxyhypusine synthase (DHPS) to eIF5A^Hyp, influences inflammatory gene expression.

Purpose of the Study:

• To investigate the role of DHPS and eIF5A^Hyp in the meta-inflammation of obesity.
• To determine if DHPS impacts macrophage phenotype and inflammatory signaling pathways.

Main Methods:

• Quantified eIF5A^Hyp levels in adipose tissue macrophages from obese mice and activated murine macrophages.
• Utilized global proteomics and transcriptomics in DHPS-deficient macrophages.
• Assessed the impact of DHPS deficiency in myeloid cells on macrophage infiltration and glucose tolerance in obese mice.

Main Results:

• eIF5A^Hyp levels were elevated in adipose tissue macrophages of obese mice and M1-activated macrophages.
• DHPS deficiency in macrophages altered protein abundance in NF-κB signaling pathways, suggesting translational control.
• DHPS deficiency in myeloid cells of obese mice reduced M1 macrophage accumulation and improved glucose tolerance.

Conclusions:

• DHPS plays a critical role in the post-transcriptional regulation of inflammatory and chemotactic mRNAs in macrophages.
• DHPS contributes to the development of a proinflammatory M1-like macrophage phenotype, driving meta-inflammation in obesity.
• Targeting DHPS may offer a therapeutic strategy for managing obesity-related metabolic dysfunction.