Rheumatoid arthritis synovial microenvironment induces metabolic and functional adaptations in dendritic cells

Area of Science:

• Immunology
• Rheumatology
• Cell Biology

Background:

• Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cartilage and bone degradation.
• Inflammatory cell influx into the joint is a hallmark of RA pathogenesis.
• The specific role of dendritic cells (DCs) and the impact of the synovial microenvironment on their maturation in RA remain underexplored.

Purpose of the Study:

• To investigate the role of the RA synovial microenvironment in dendritic cell (DC) maturation.
• To explore the metabolic reprogramming of DCs within this environment.
• To identify potential signaling pathways involved in these processes.

Main Methods:

• An in-vitro model using monocyte-derived DCs (MoDCs) treated with explant-conditioned media (ECM) from synovial tissue.
• Analysis of DC maturation markers (CD83, CCR7, CCR5) and phagocytic capacity.
• Assessment of cellular bioenergetics, including gene expression of glycolytic pathways and glucose uptake.
• Inhibition of signal transducer and activator of transcription-3 (STAT-3) to evaluate its role.
• RNA sequencing (RNA-seq) of DCs from RA synovial fluid and peripheral blood.

Main Results:

• ECM-treated MoDCs exhibited increased expression of maturation markers (CD83, CCR7), pro-inflammatory cytokines, chemokines, and adhesion molecules.
• ECM-induced DCs showed decreased CCR5 expression and reduced phagocytic capacity, indicating heightened maturation.
• A metabolic shift towards glycolysis was observed in ECM-treated DCs, with increased glycolytic gene expression and glucose uptake.
• STAT-3 inhibition reduced pro-inflammatory cytokine and glycolytic gene expression in ECM-treated DCs.
• RNA-seq revealed enhanced expression of glycolytic genes in synovial CD1c+ DCs compared to circulating counterparts.

Conclusions:

• The RA synovial microenvironment drives DC maturation and metabolic reprogramming, favoring glycolysis.
• STAT-3 signaling plays a partial role in mediating these RA-induced DC adaptations.
• These findings highlight a novel mechanism of DC dysfunction in RA pathogenesis and suggest potential therapeutic targets.