GRK2-mediated phosphorylation and de-succinylation of PKM2 reduce macrophage glycolysis in rheumatoid arthritis

Area of Science:

• Biochemistry
• Immunology
• Metabolic disease

Background:

• Glucose metabolism disorder is a key feature of rheumatoid arthritis (RA).
• Current treatments targeting glycolytic metabolism in RA are limited.
• G protein-coupled receptor kinase 2 (GRK2) is a regulatory hub with potential therapeutic relevance.

Purpose of the Study:

• To investigate the role of GRK2 inhibition in regulating glycolysis in monocyte-derived macrophages (MDMs) from RA patients.
• To explore GRK2's mechanism in controlling key glycolytic enzymes, particularly PKM2.
• To evaluate GRK2 inhibitors as a potential therapeutic strategy for RA-associated metabolic dysregulation.

Main Methods:

• Isolation and differentiation of human peripheral mononuclear cells into MDMs.
• Analysis of metabolic status in RA MDMs under normoxia and hypoxia.
• Proteomics and mass spectrometry to identify GRK2 targets.
• In vitro and in vivo studies using GRK2 inhibitors in a collagen-induced arthritis (CIA) mouse model.

Main Results:

• Glycolysis is elevated in RA MDMs, and its inhibition suppresses macrophage inflammation.
• GRK2 directly inhibits key glycolytic enzymes, including PKM2, by maintaining its tetramer stability via phosphorylation and de-succinylation.
• Reduced cytoplasmic GRK2 levels in RA lead to increased glycolysis and disease progression.
• GRK2 inhibitors (paroxetine, CP-25) and a glycolysis inhibitor (2-DG) restored GRK2 levels and improved metabolic regulation in a CIA mouse model.

Conclusions:

• GRK2 plays a critical role in suppressing glycolysis in macrophages.
• Dysregulation of GRK2 contributes to enhanced glycolysis and RA progression.
• Targeting GRK2 represents a promising therapeutic avenue for managing RA by modulating glucose metabolism.