Roxadustat enhances inflammation and metabolic reprogramming in human leukocytes by affecting oxygen sensing

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, such as roxadustat, are approved for treating anemia in chronic kidney disease.
• The effects of HIF stabilization on circulating leukocytes are not well understood.

Purpose of the Study:

• To investigate the impact of roxadustat on human peripheral blood mononuclear cells (PBMCs).
• To explore roxadustat's effects on leukocyte viability, HIF pathway activation, metabolic shifts, and immune cell dynamics.

Main Methods:

• Assessed PBMC viability, HIF pathway activation (protein and gene expression), and metabolic changes (oxygen consumption, extracellular acidification).
• Utilized single-cell RNA sequencing to analyze immune subpopulation dynamics and activation.
• Investigated combined effects of roxadustat and lipopolysaccharide to model inflammatory hypoxia.

Main Results:

• Roxadustat did not affect PBMC viability but induced HIF-1α accumulation and glycolytic reprogramming.
• Gene expression analysis revealed significant cytokine production.
• Single-cell RNA sequencing demonstrated shifts in leukocyte subpopulations and an amplified inflammatory response when combined with lipopolysaccharide.

Conclusions:

• Roxadustat acts as an immune modulator, potentially activating specific leukocyte subsets and enhancing inflammatory responses.
• These findings highlight the immunological effects of HIF stabilization and warrant further investigation into roxadustat's therapeutic and safety profile in patient care.