Metabolic checkpoints in rheumatoid arthritis

Area of Science:

• Immunology
• Metabolic pathways
• Autoimmune diseases

Background:

• Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 0.5-1% of the population.
• Despite advancements, RA remains incurable, causing significant morbidity.
• HLA class II polymorphisms highlight T cells as key drivers, while innate immune cells like macrophages (MΦ) contribute to inflammation.

Purpose of the Study:

• To summarize metabolic conditions within the RA joint.
• To elucidate metabolic circuits influencing RA T cells and MΦ effector functions.

Main Methods:

• Review of current knowledge on cellular metabolism in rheumatoid arthritis.
• Analysis of metabolic adaptations in T cells and macrophages within the RA joint environment.

Main Results:

• The RA joint is glucose-depleted, favoring cells utilizing non-glucose fuels like glutamine.
• RA T cells exhibit low mitochondrial function, impaired ATP production, and increased autoreactivity due to mtDNA repair defects.
• RA macrophages display highly functional mitochondria, upregulated HLA-DR, and enhanced glutaminolysis via RFX5 and GLUD1 for antigen presentation and survival.

Conclusions:

• Metabolic reprogramming is critical for immune cell survival and function in the RA joint.
• These adaptations promote immunostimulation, tissue invasion, and sustain rheumatoid synovitis.
• Targeting cellular metabolism presents a potential therapeutic strategy for RA.