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

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease which causes degradation of cartilage and bone. It is well appreciated that the pathogenic hallmark of RA is the mass influx of inflammatory cells into the joint. However, the role that dendritic cells (DC) may play in this inflammatory milieu is still relatively unexplored. Moreover, the contribution this unique synovial microenvironment has on DC maturation is still unknown. Using monocyte-derived DC (MoDC), we established an in-vitro model to recapitulate the synovial microenvironment to explore DC maturation. MoDC treated with conditioned media from ex-vivo synovial tissue biopsy cultures [explant-conditioned media (ECM)] have increased expression of proinflammatory cytokines, chemokines and adhesion molecules. ECM DC have increased expression of CD83 and CC-chemokine receptor (CCR)7 and decreased expression of CCR5 and phagocytic capacity, suggestive of heightened DC maturation. ECM-induced maturation is concomitant with altered cellular bioenergetics, whereby increased expression of glycolytic genes and increased glucose uptake are observed in ECM DC. Collectively, this results in a metabolic shift in DC metabolism in favour of glycolysis. These adaptations are in-part mediated via signal transducer and activator of transcription-3 (STAT-3), as demonstrated by decreased expression of proinflammatory cytokines and glycolytic genes in ECM DC in response to STAT-3 inhibition. Finally, to translate these data to a more in-vivo clinically relevant setting, RNA-seq was performed on RA synovial fluid and peripheral blood. We identified enhanced expression of a number of glycolytic genes in synovial CD1c+ DC compared to CD1c+ DC in circulation. Collectively, our data suggest that the synovial microenvironment in RA contributes to DC maturation and metabolic reprogramming.